Anemia

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Overview
Anemia (American English) or anæmia/anaemia (British English), from the Greek (an-haîma) meaning "without blood", is a deficiency of red blood cells (RBCs) and/or hemoglobin. This results in a reduced ability of blood to transfer oxygen to the tissues, causing tissue hypoxia. Since all human cells depend on oxygen for survival, varying degrees of anemia can have a wide range of clinical consequences. Hemoglobin (the oxygen-carrying protein in the red blood cells) has to be present to ensure adequate oxygenation of all tissues and organs. The three main classes of anemia include excessive blood loss (acutely such as a hemorrhage or chronically through low-volume loss), excessive blood cell destruction (hemolysis) or deficient red blood cell production (ineffective hematopoiesis).

Anemia is the most common disorder of the blood. There are several kinds of anemia, produced by a variety of underlying causes. Anemia can be classified in a variety of ways, based on the morphology of RBCs, underlying etiologic mechanisms, and discernible clinical spectra, to mention a few.

There are two major approaches of classifying anemias, the "kinetic" approach which involves evaluating production, destruction and loss, and the "morphologic" approach which groups anemia by red blood cell size. The morphologic approach uses a quickly available and cheap lab test as its starting point (the MCV). On the other hand, focusing early on the question of production may allow the clinician more rapidly to expose cases where multiple causes of anemia coexist.

Signs and symptoms
Anemia goes undetected in many people, and symptoms can be vague. Most commonly, people with anemia report a feeling of weakness or fatigue in general or during exercise, general malaise and sometimes poor concentration. People with more severe anemia often report dyspnea (shortness of breath) on exertion. Very severe anemia prompts the body to compensate by increasing cardiac output, leading to palpitations and sweatiness, and to heart failure.

Pallor (pale skin, mucosal linings and nail beds) is often a useful diagnostic sign in moderate or severe anemia, but it is not always apparent. Other useful signs are cheilosis and koilonychia.

Pica, the consumption of non-food such as dirt, paper, wax, grass and hair, 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 scholastic performance in children of school age. Behavioral disturbances may even surface as an attention deficit disorder.

Diagnosis
Generally, clinicians request complete blood counts in the first batch of blood tests in the diagnosis of an anemia. Apart from reporting the number of red blood cells and the hemoglobin level, the automatic counters also measure the size of the red blood cells by flow cytometry, which is an important tool in distinguishing between the causes of anemia. Examination of a stained blood smear using a microscope can also be helpful, and is sometimes a necessity in regions of the world where automated analysis is less accessible.

In modern counters, four parameters (RBC Count, hemoglobin concentration, Mean Corpuscular Volume or MCV and Red blood cell distribution width or RDW) are measured, allowing others (hematocrit, Mean corpuscular hemoglobin or MCH and Mean corpuscular hemoglobin concentration or MCHC) to be calculated, and compared to values adjusted for age and sex. Some counters estimate hematocrit from direct measurements. For adult men, a hemoglobin level less than 13.0 g/dl is diagnostic of anemia, and for adult women, the diagnostic threshold is  below 12.0 g/dl.

Reticulocyte counts, and the "kinetic" approach to anemia, have become more common than in the past in the large medical centers of the United States and some other wealthy nations, in part because some automatic counters now have the capacity to include reticulocyte counts. A reticulocyte count is a quantitative measure of the bone marrow's production of new red blood cells. The reticulocyte production index is a calculation of the ratio between the level of anemia and the extent to which the reticulocyte count has risen in response. If the degree of anemia is significant, even a "normal" reticulocyte count actually may reflect an inadequate response.

If an automated count is not available, a reticulocyte count can be done manually following special staining of the blood film. In manual examination, activity of the bone marrow can also be gauged qualitatively by subtle changes in the numbers and the morphology of young RBCs by examination under a microscope. Newly formed RBCs are usually slightly larger than older RBCs and show polychromasia. Even where the source of blood loss is obvious, evaluation of erythropoiesis can help assess whether the bone marrow will be able to compensate for the loss, and at what rate.

When the cause is not obvious, clinicians use other tests: ESR, ferritin, serum iron, transferrin, RBC folate level, serum vitamin B12, hemoglobin electrophoresis, renal function tests (e.g. serum creatinine).

When the diagnosis remains difficult, a bone marrow examination allows direct examination of the precursors to red cells.

Macrocytic

 * Acute leukemia
 * Addison's Disease
 * Alcohol
 * Chronic nephropathy
 * Chronic inflammation/infection
 * Chronic liver disease
 * Crohn's Disease
 * Drugs
 * Oral contraceptives
 * Neomycin
 * Aciclovir
 * Folic acid antagonists
 * 5-FU
 * Triamterene
 * Trimethoprim
 * Colchicine
 * Folate deficiency
 * Hemodialysis
 * Hemolytic anemia
 * HIV
 * Hyperthyroidism
 * Hypothyroidism
 * Intoxication
 * Ionizing radiation
 * Kidney Disease
 * Liver Disease
 * Malignant tumors
 * Malabsorption
 * Malnutrition
 * Malnutrition
 * Vegetarianism
 * Marrow infiltration
 * Megaloblastic anemia
 * Methylmalonyl-CoA mutase
 * Multiple Myeloma
 * Myeloproliferative Diseases
 * Myelodysplastic Syndrome
 * Pernicious anemia
 * Pregnancy
 * Sprue
 * Vitamin B12 Deficiency

Microcytic

 * Atransferrinemia
 * Anemia of chronic disease
 * Hypothyroidism
 * Infection, inflammation, neoplastic causes of anemia
 * Iron deficiency anemia
 * Insufficient resorption
 * Insufficient supply
 * Increased requirements
 * Iron loss
 * Lead poisoning
 * Myeloproliferative syndrome
 * Pituitary insufficiency
 * Protein deficiency
 * Sideroblastic anemia
 * Thalassemia
 * Vitamin deficiencies

Normocytic

 * Acanthocytosis
 * Addison's Disease
 * Aluminum intoxication
 * Anemia of chronic disease
 * Aplastic Anemia
 * Autoimmune diseases
 * Autoimmune hemolytic anemia
 * Babesiosis
 * Bartonellosis
 * Blackfan-Diamond Syndrome
 * Bone marrow disease
 * Chemicals:
 * Insect and snake venom
 * Gasoline
 * Benzenes
 * Bacterial toxins
 * Cholera
 * Clostridia
 * Congenital lipid disorders
 * Copper intoxication Wilson's disease
 * Disseminated intravascular coagulation
 * Drugs:
 * Penicillin
 * Clonidine
 * Phenacetin
 * Sulfonamides
 * Pyramidone
 * Chloroporemazine
 * Alpha-methyldopa
 * Isoniazid
 * Elliptocytosis
 * Enzyme defects
 * Erythropoietic porphyrias
 * Folate deficiency
 * G6PD deficiency (glucose 6-phosphate dehydrogenase)
 * Hemorrhage
 * Hereditary Spherocytosis
 * HIV
 * Hypogonadism
 * Hypoparathyroidism
 * Hypothyroidism
 * Impaired hemoglobin synthesis/pathologic hemoglobins
 * Infection
 * Iron deficiency anemia
 * Isoimmunohemolytic anemia
 * Liver Disease
 * Malaria
 * Mechanical hemolysis
 * Membrane defects
 * Microangiopathy
 * Osteomyelofibrosis
 * Panhypopituitarism
 * Panmyelopathy
 * Paroxysmal nocturnal hemoglobinuria
 * Pregnancy
 * Pure red cell aplasia
 * Red cell trauma
 * Renal Insufficiency
 * Sepsis
 * Sickle cell Disease
 * Spherocytosis
 * Taxoplasmosis
 * Thalassemia Syndrome
 * Thermal erthrocyte damage (burns)
 * Uremia
 * Vitamin B12 deficiency
 * Wilson's Disease
 * Zieve's Syndrome

Classification
One of the most common systems classifies anemia based upon the size of the red blood cells and the concentration of hemoglobin in the red blood cells:

Mean corpuscular volume (MCV)
MCV is used to distinguish between microcytic, normocytic, and macrocytic anemia.
 * Microcytic: MCV<80
 * Normocytic: MCV 80-100
 * Macrocytic: MCV>100

Mean corpuscular hemoglobin concentration (MCHC)
MCHC is used to distinguish between hypochromic, normochromic, and hyperchromic anemia.
 * Hypochromic: MCHC<33
 * Normochromic: MCHC 33-35
 * Hyperchromic: MCHC>35

Production vs. destruction or loss
The "kinetic" approach to anemia yields what many argue is the most clinically relevant classification of anemia. This classification depends on evaluation of several hematological parameters, particularly the blood reticulocyte (precursor of mature RBCs) count. This then yields the classification of defects by decreased RBC production versus increased RBC destruction and/or loss. Clinical signs of loss or destruction include abnormal peripheral blood smear with signs of hemolysis; elevated LDH suggesting cell destruction; or clinical signs of bleeding, such as guiaic-positive stool, radiographic findings, or frank bleeding.

Here is a simplified schematic of this approach:

* For instance, sickle cell anemia with superimposed iron deficiency; chronic gastric bleeding with B12 and folate deficiency; and other instances of anemia with more than one cause. ** Confirm by repeating reticulocyte count: ongoing combination of low reticulocyte production index, normal MCV and hemolysis or loss may be seen in bone marrow failure or anemia of chronic disease, with superimposed or related hemolysis or blood loss.

Red blood cell size
In the morphological approach, anemia is classified by the size of red blood cells; this is either done automatically or on microscopic examination of a peripheral blood smear. The size is reflected in the mean corpuscular volume (MCV). If the cells are smaller than normal (under 80 fl), the anemia is said to be microcytic; if they are normal size (80-100 fl), normocytic; and if they are larger than normal (over 100 fl), the anemia is classified as macrocytic. This scheme quickly exposes some of the most common causes of anemia; for instance, a microcytic anemia is often the result of iron deficiency. In clinical workup, the MCV will be one of the first pieces of information available; so even among clinicians who consider the "kinetic" approach more useful philosophically, morphology will remain an important element of classification and diagnosis.

Here is a schematic representation of how to consider anemia with MCV as the starting point:

Other characteristics visible on the peripheral smear may provide valuable clues about a more specific diagnosis; for example, abnormal white blood cells may point to a cause in the bone marrow.

Microcytic anemia
Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies:
 * Heme synthesis defect
 * Iron deficiency
 * Anemia of Chronic Disorders (more commonly presenting as normocytic anemia)
 * Globin synthesis defect
 * alpha-, and beta-thalassemia
 * HbE syndrome
 * HbC syndrome
 * and various other unstable hemoglobin diseases
 * Sideroblastic defect
 * Hereditary Sideroblastic anemia
 * Acquired Sideroblastic anemia including lead toxicity
 * Reversible Sideroblastic anemia


 * Iron deficiency anemia is the most common type of anemia overall and it has many causes. RBCs often appear hypochromic (paler than usual) and microcytic (smaller than usual) when viewed with a microscope.
 * Iron deficiency anemia is caused by insufficient dietary intake or absorption of iron to replace losses from menstruation or losses due to diseases. Iron is an essential part of hemoglobin, and low iron levels result in decreased incorporation of hemoglobin into red blood cells. In the United States, 20% of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men. The principal cause of iron deficiency anemia in premenopausal women is blood lost during menses. Studies have shown that iron deficiency without anemia causes poor school performance and lower IQ in teenage girls. Iron deficiency is the most prevalent deficiency state on a worldwide basis.   Iron found in animal meats are more easily absorbed by the body than iron found in non-meat sources. In countries where animal meats are only occasionally available in the diet, iron deficiency anemia is six to eight times more prevalent than in North America and Europe.  Iron deficiency is sometimes the cause of abnormal fissuring of the angular (corner) sections of the  lips (angular cheilitis).
 * Iron deficiency anemia can also be due to bleeding lesions of the gastrointestinal tract. Fecal occult blood testing, upper endoscopy and lower endoscopy should be performed to identify bleeding lesions. In men and post-menopausal women the chances are higher that bleeding from the gastrointestinal tract could be due to colon polyp or colorectal cancer.
 * Worldwide, the most common cause of iron deficiency anemia is parasitic infestation (hookworm, amebiasis, schistosomiasis and whipworm).
 * Hemoglobinopathies - much rarer (apart from communities where these conditions are prevalent)


 * Hb S Sickle-cell disease
 * Hb C
 * Hb E
 * Hb D-Punjab
 * Hb O-Arab
 * Hb G-Philadelphia
 * Hb Hasharon
 * Hb Korle-Bu
 * Hb Lepore
 * Hb M

A mnemonic commonly used to remember causes of microcytic anemia is TAILS: T - Thalassemia, A - Anemia of chronic disease, I - Iron deficiency anemia, L - Lead toxicity associated anemia, S - Sideroblastic anemia.

Normocytic anemia
Normocytic anaemia occurs when the overall Hb levels are decreased, but the red blood cell size (MCV) remains normal. Causes include:
 * Acute blood loss
 * Anemia of chronic disease
 * Aplastic anemia (bone marrow failure)
 * Hemolytic anemia

Macrocytic anemia

 * Megaloblastic anemia is the most common cause of macrocytic anemia.
 * Megaloblastic anemia is due to a deficiency of either vitamin B12, folic acid (or both), or to autoimmune processes that cause deficiency in either, such as pernicious anemia. Deficiency in folate and/or Vitamin B12 can be due either to inadequate intake or insufficient absorption. Folate deficiency normally does not produce neurological symptoms, while B12 deficiency does.
 * Pernicious anemia is an autoimmune condition directed against the parietal cells of the stomach. Parietal cells produce intrinsic factor, required to absorb vitamin B12 from food. Therefore, the destruction of the parietal cells causes a lack of intrinsic factor, leading to poor absorption of vitamin B12. Pernicious anemia can also be caused by removal of the functional portion of the stomach, such as during gastric bypass surgery. Therefore one must always be aware of anemia following this procedure.
 * Alcoholism causes a macrocytosis, although not specifically anemia
 * Methotrexate, zidovudine, and other drugs that inhibit DNA replication. This is the most common etiology in nonalcoholic patients.

Macrocytic anemia can be further divided into "megaloblastic anemia" or "non-megaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (6-10 lobes). The non-megaloblastic macrocytic anemias have different etiologies (i.e. there is unimpaired DNA globin synthesis,) which occur, for example in alcoholism.

In addition to the non-specific symptoms of anemia, specific features of vitamin B12 deficiency include peripheral neuropathy and subacute combined degeneration of the cord with resulting balance difficulties from posterior column spinal cord pathology. Other features may include a smooth, red tongue, (glossitis).

The treatment for vitamin B12-deficient anemia was first devised by William Murphy who bled dogs to make them anemic and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set about to chemically isolate the curative substance and ultimately were able to isolate the vitamin B12 from the liver. All three shared the 1934 Nobel Prize in Medicine.

Dimorphic anemia
When two causes of anemia act simultaneously, e.g., macrocytic hypochromic, due to hookworm infestation leading to deficiency of both iron and vitamin B12 or folic acid or following a blood transfusion more than one abnormality of red cell indices may be seen. Evidence for multiple causes appears with an elevated RBC distribution width (RDW), which suggests a wider-than-normal range of red cell sizes.

Heinz body anemia
Heinz bodies are an abnormality that form on the cells in this condition. This form of anemia may be brought on by taking certain medications; it is also triggered in cats by eating onions. or acetaminophen (Tylenol). It can be triggered in dogs by ingesting onions or zinc, and in horses by ingesting dry Red Maple leaves.

Specific anemias

 * Anemia of prematurity occurs in premature infants at 2 to 6 weeks of age and results from diminished erythropoietin response to declining hematocrit levels
 * Fanconi anemia is an hereditary disorder or defect featuring aplastic anemia and various other abnormalities
 * Hemolytic anemia causes a separate constellation of symptoms (also featuring jaundice and elevated LDH levels) with numerous potential causes. It can be autoimmune, immune, hereditary or mechanical (e.g. heart surgery). It can result (because of cell fragmentation) in a microcytic anemia, a normochromic anemia, or (because of premature release of immature red blood cells from the bone marrow), a macrocytic anemia.
 * Hereditary spherocytosis is a hereditary defect that results in defects in the RBC cell membrane, causing the erythrocytes to be sequestered and destroyed by the spleen. This leads to a decrease in the number of circulating RBCs and, hence, anemia.
 * Sickle-cell anemia, a hereditary disorder, is due to homozygous hemoglobin S genes.
 * Warm autoimmune hemolytic anemia is an anemia caused by autoimmune attack against red blood cells, primarily by IgG
 * Cold agglutinin hemolytic anemia is primarily mediated by IgM
 * Pernicious anemia is a form of megaloblastic anaemia due to vitamin B12 deficiency dependent on impaired absorption of vitamin B12.
 * Myelophthisic anemia or Myelophthisis is a severe type of anemia resulting from the replacement of bone marrow by other materials, such as malignant tumors or granulomas.

Possible complications
Anemia diminishes the capability of individuals who are affected to perform physical activities. This is a result of one's muscles being forced to depend on anaerobic metabolism. The lack of iron associated with anemia can cause many complications, including hypoxemia, brittle or rigid fingernails, cold intolerance, impaired immune function, and possible behavioral disturbances in children.

Hypoxemia resulting from anemia can worsen the cardio-pulmonary status of patients with pre-existing chronic pulmonary disease. Brittle or rigid fingernails may be a result of abnormal thinness of nails due to insufficient iron supply. Cold intolerance occurs in one in five patients with iron deficiency anemia, and becomes visible through numbness and tingling. Impaired immune functioning leading to increased likelihood of sickness is another possible complication.

Anemia during pregnancy
Anemia affects 20% of all females of childbearing age in the United States. Because of the subtlety of the symptoms, women are often unaware that they have this disorder, as they attribute the symptoms to the stresses of their daily lives. Possible problems for the fetus include increased risk of growth retardation, prematurity, intrauterine death, rupture of the amnion and infection.

During pregnancy, women should be especially aware of the symptoms of anemia, as an adult female loses an average of two milligrams of iron daily. Therefore, she must intake a similar quantity of iron in order to make up for this loss. Additionally, a woman loses approximately 500 milligrams of iron with each pregnancy, compared to a loss of 4-100 milligrams of iron with each period. Possible consequences for the mother include cardiovascular symptoms, reduced physical and mental performance, reduced immune function, tiredness, reduced peripartal blood reserves and increased need for blood transfusion in the postpartum period.

Diet and anemia
Consumption of food rich in iron is essential to prevention of iron deficiency anemia.

Some foods rich in iron include: Canned clams; Fortified dry cereals; Cooked oysters; Organ meats (liver, giblets); *Fortified instant cooked cereals; Soybeans, mature, cooked; Pumpkin and squash seed kernels, roasted; White beans; Blackstrap molasses, 1 Tbsp; Lentils, cooked; Spinach, cooked from fresh; Beef (chuck); Kidney beans; Sardines; Beef(rib); Chickpeas; Duck, meat only; Lamb shoulder; Prune juice.

Certain foods have been found to interfere with iron absorption in the gastrointestinal tract, and these foods should be avoided in persons with established iron deficiency. They include tea, coffee, wheat bran, rhubarb, chocolate, chewing gum, red wine, and dairy products.

Initial Studies

 * Bilirubin
 * Blood urea nitrogen or BUN
 * Complete blood count (CBC)
 * MCV
 * MCHC
 * RDW (red cell distribution width)
 * Creatinine
 * Fecal occult blood test
 * Iron studies
 * Lactate dehydrogenase (LDH)
 * Peripheral smear
 * Reticulocyte count

Follow-up Studies Depending Upon Clinical Suspicion

 * Antiparietal cell antibodies
 * Anti-intrinsic factor antibodies
 * Folate levels
 * Liver function tests (LFTs)
 * Thyroid stimulating hormone (TSH)
 * Free erythrocyte protoporphyrin
 * Haptoglobin
 * Faecal microscopy
 * Urinalysis
 * Vitamin B12 levels
 * Hemoglobin electrophoresis

Treatment of Anemia
If hemodynamic compromise is present, then immediate intervention is required which includes:
 * Administration of O2 as needed
 * Iron, folate, vitamin B12 supplements as necessary
 * IV fluids for maintenance of blood pressure
 * For hemoglobins <8 gm/dl, blood transfusions are indicated
 * Establishment of two large-bore IVs for cases of ongoing acute blood loss

There are many different treatments for anemia and the treatment depends on severity and the cause.

Iron deficiency from nutritional causes is rare in non-menstruating adults (men and post-menopausal women). The diagnosis of iron deficiency mandates a search for potential sources of loss such as gastrointestinal bleeding from ulcers or colon cancer. Mild to moderate iron deficiency anemia is treated by iron supplementation with ferrous sulfate or ferrous gluconate. Vitamin C may aid in the body's ability to absorb iron.

Vitamin supplements given orally (folic acid) or subcutaneously (vitamin b-12) will replace specific deficiencies.

In anemia of chronic disease, anemia associated with chemotherapy, or anemia associated with renal disease, some clinicians prescribe recombinant erythropoietin, epoetin alfa, to stimulate red cell production.

In severe cases of anemia, or with ongoing blood loss, a blood transfusion may be necessary.

Blood transfusions for anemia
Doctors attempt to avoid blood transfusion in general, since multiple lines of evidence point to increased adverse patient clinical outcomes with more intensive transfusion strategies. The physiological principle that reduction of oxygen delivery associated with anemia leads to adverse clinical outcomes is balanced by the finding that transfusion does not necessarily mitigate these adverse clinical outcomes.

In severe, acute bleeding, transfusions of donated blood are often lifesaving. Improvements in battlefield casualty survival is attributable, at least in part, to the recent improvements in blood banking and transfusion techniques.

Transfusion of the stable but anemic hospitalized patient has been the subject of numerous clinical trials, and transfusion is emerging as a deleterious intervention.

Four randomized controlled clinical trials have been conducted to evaluate aggressive versus conservative transfusion strategies in critically ill patients. All four of these studies failed to find a benefit with more aggressive transfusion strategies.

In addition, at least two retrospective studies have shown increases in adverse clinical outcomes with more aggressive transfusion strategies.

On the whole, these studies suggest that aggressive transfusions, at least for hospitalized patients, may at best not improve any clinical parameter, and at worst lead to adverse outcomes.

A recent report suggests that the culprit is the depletion of nitric oxide, an important vasodilator, in banked blood. The theory is that the transfusion of nitric oxide-depleted blood causes systemic vasoconstriction, and exacerbates hypoxia in tissues at risk.