Anemia

Anemia
Other names	Anaemia, erythrocytopenia
Blood loss, decreased red blood cell production, increased red blood cell breakdown[1]
Diagnostic method	Blood hemoglobin measurement[1]
Frequency	2.36 billion / 33% (2015)[2]

Anemia or anaemia (

The name is derived from When anemia comes on slowly, the symptoms are often vague, such as tiredness, weakness, shortness of breath, headaches, and a reduced ability to exercise.^[1] When anemia is acute, symptoms may include confusion, feeling like one is going to pass out, loss of consciousness, and increased thirst.^[1] Anemia must be significant before a person becomes noticeably pale.^[1] Additional symptoms may occur depending on the underlying cause.^[1] Anemia can be temporary or long term and can range from mild to severe.^[6]

Anemia can be caused by

Treatment depends on the specific cause. Certain groups of individuals, such as pregnant women, can benefit from the use of

Anemia is the most common blood disorder, affecting about a fifth to a third of the global population.

Signs and symptoms

A person with anemia may not have any symptoms, depending on the underlying cause, and no symptoms may be noticed, as the anemia is initially mild, and then the symptoms become worse as the anemia worsens. A patient with anemia may report feeling tired, weak, decreased ability to concentrate, and sometimes shortness of breath on exertion.^[19] These symptoms are unspecific and none of the symptoms alone or in combination show a good predictive value for the presence of anemia in non-clinical patients.^[20]

Symptoms of anemia can come on quickly or slowly.

In more severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing

On examination, the signs exhibited may include

. Pica, the consumption of non-food items such as ice, paper, wax, grass, hair or dirt, may be a symptom of iron deficiency;^[25] 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 people with iron-deficiency anemia than in the general population.^[26]

Causes

The causes of anemia may be classified as impaired red blood cell (RBC) production, increased RBC destruction (hemolytic anemia), blood loss and fluid overload (hypervolemia). Several of these may interplay to cause anemia. The most common cause of anemia is blood loss, but this usually does not cause any lasting symptoms unless a relatively impaired RBC production develops, in turn, most commonly by iron deficiency.^[4]

Impaired production

• Disturbance of proliferation and differentiation of stem cells
  • Pure red cell aplasia^[28]
  • Aplastic anemia^[28] affects all kinds of blood cells. Fanconi anemia is a hereditary disorder or defect featuring aplastic anemia and various other abnormalities.
  • Anemia of kidney failure^[28] due to insufficient production of the hormone erythropoietin
  • Anemia of endocrine disease^[29]
• Disturbance of proliferation and maturation of
  erythroblasts
  • Pernicious anemia^[28] is a form of megaloblastic anemia due to vitamin B₁₂ deficiency dependent on impaired absorption of vitamin B₁₂. Lack of dietary B₁₂ causes non-pernicious megaloblastic anemia.
  • Anemia of
    folate deficiency,^[28] as with vitamin B₁₂, causes megaloblastic anemia
  • Anemia of prematurity, by diminished erythropoietin response to declining hematocrit levels, combined with blood loss from laboratory testing, generally occurs in premature infants at two to six weeks of age.
  • Iron-deficiency anemia, resulting in deficient heme synthesis^[28]
  • Thalassemias, causing deficient globin synthesis^[28]
  • Congenital dyserythropoietic anemias, causing ineffective erythropoiesis
  • Anemia of kidney failure^[28] (also causing stem cell dysfunction)
• Other mechanisms of impaired RBC production
  • myelophthisis
    is a severe type of anemia resulting from the replacement of bone marrow by other materials, such as malignant tumors, fibrosis, or granulomas.
  • Myelodysplastic syndrome^[28]
  • anemia of
    chronic inflammation^[28]
  • Leukoerythroblastic anemia is caused by space-occupying lesions in the bone marrow that prevent normal production of blood cells.^[30]

Increased destruction

Anemias of increased red blood cell destruction are generally classified as hemolytic anemias. These types generally feature jaundice, and elevated levels of lactate dehydrogenase.^[31][32]

• Intrinsic (intracorpuscular) abnormalities^[28] cause premature destruction. All of these, except paroxysmal nocturnal hemoglobinuria, are hereditary genetic disorders.^[33]
  • Hereditary spherocytosis^[28] is a hereditary defect that results in defects in the RBC cell membrane, causing the erythrocytes to be sequestered and destroyed by the spleen.
  • Hereditary elliptocytosis^[28] is another defect in membrane skeleton proteins.
  • Abetalipoproteinemia,^[28] causing defects in membrane lipids
  • Enzyme deficiencies
    • Pyruvate kinase and hexokinase deficiencies,^[28] causing defect glycolysis
    • Glucose-6-phosphate dehydrogenase deficiency and glutathione synthetase deficiency,^[28] causing increased oxidative stress
  • Hemoglobinopathies
    • Sickle cell anemia^[28]
    • Hemoglobinopathies causing unstable hemoglobins[28]
  • Paroxysmal nocturnal hemoglobinuria^[28]
• Extrinsic (extracorpuscular) abnormalities
  • Antibody-mediated
    • systemic lupus erythematosus, or a malignancy, such as chronic lymphocytic leukemia.^[35]
    • Cold agglutinin hemolytic anemia is primarily mediated by IgM. It can be idiopathic^[36]
      or result from an underlying condition.
    • Rh disease,^[28] one of the causes of hemolytic disease of the newborn
    • Transfusion reaction to blood transfusions^[28]
  • Mechanical trauma to red blood cells
    • Microangiopathic hemolytic anemias, including thrombotic thrombocytopenic purpura and disseminated intravascular coagulation^[28]
    • Infections, including malaria^[28]
    • Heart surgery^{[medical citation needed}
      ]
    • Haemodialysis^{[medical citation needed}
      ]
  • Parasitic
    • Trypanosoma congolense alters the surfaces of RBCs of its host and this may explain T. c. induced anemia^[37]

Blood loss

• Anemia of prematurity, from frequent blood sampling for laboratory testing, combined with insufficient RBC production
• Trauma^[28] or surgery
  , causing acute blood loss
• Gastrointestinal tract lesions,
  peptic ulcers, hemorrhoids^[38]) or chronic blood loss (e.g. angiodysplasia
  )
• Gynecologic disturbances,[28] also generally causing chronic blood loss
• From menstruation, mostly among young women or older women who have fibroids
• Many type of cancers, including colorectal
  urinary bladder
  , may cause acute or chronic blood loss, especially at advanced stages
• Infection by intestinal
  nematodes feeding on blood, such as hookworms^[39] and the whipworm Trichuris trichiura ^[40]
• Iatrogenic anemia, blood loss from repeated blood draws and medical procedures.^[41][42]

The roots of the words anemia and ischemia both refer to the basic idea of "lack of blood", but anemia and

Fluid overload

Fluid overload (hypervolemia) causes decreased hemoglobin concentration and apparent anemia:^[44]

• General causes of hypervolemia include excessive sodium or fluid intake, sodium or water retention and fluid shift into the intravascular space.^[45]
• From the 6th week of pregnancy, hormonal changes cause an increase in the mother's blood volume due to an increase in plasma.^[46]

Intestinal inflammation

Certain gastrointestinal disorders can cause anemia. The mechanisms involved are multifactorial and not limited to malabsorption but mainly related to chronic intestinal inflammation, which causes dysregulation of hepcidin that leads to decreased access of iron to the circulation.^[47][48][49]

• Helicobacter pylori infection.^[50]
• Gluten-related disorders: untreated
  celiac disease^[49][50] and non-celiac gluten sensitivity.^[51] Anemia can be the only manifestation of celiac disease, in absence of gastrointestinal or any other symptoms.^[52]
• Inflammatory bowel disease.^[53][54]

Diagnosis

Definitions

There are a number of definitions of anemia; reviews provide comparison and contrast of them.^[55] A strict but broad definition is an absolute decrease in red blood cell mass,^[56] however, a broader definition is a lowered ability of the blood to carry oxygen.^[57] An operational definition is a decrease in whole-blood hemoglobin concentration of more than 2 standard deviations below the mean of an age- and sex-matched reference range.^[58]

It is difficult to directly measure RBC mass,^[59] so the hematocrit (amount of RBCs) or the hemoglobin (Hb) in the blood are often used instead to indirectly estimate the value.^[60] Hematocrit; however, is concentration dependent and is therefore not completely accurate. For example, during pregnancy a woman's RBC mass is normal but because of an increase in blood volume the hemoglobin and hematocrit are diluted and thus decreased. Another example would be bleeding where the RBC mass would decrease but the concentrations of hemoglobin and hematocrit initially remains normal until fluids shift from other areas of the body to the intravascular space.^{[citation needed]}

The anemia is also classified by severity into mild (110 g/L to normal), moderate (80 g/L to 110 g/L), and severe anemia (less than 80 g/L) in adults.^[61] Different values are used in pregnancy and children.^[61]

Testing

Anemia is typically diagnosed on a complete blood count. 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 it is sometimes a necessity in regions of the world where automated analysis is less accessible.^{[citation needed]}

WHO's Hemoglobin thresholds used to define anemia^[62] (1 g/dL = 0.6206 mmol/L)

Age or gender group	Hb threshold (g/dL)	Hb threshold (mmol/L)
Children (0.5–5.0 yrs)	11.0	6.8
Children (5–12 yrs)	11.5	7.1
Teens (12–15 yrs)	12.0	7.4
Women, non-pregnant (>15yrs)	12.0	7.4
Women, pregnant	11.0	6.8
Men (>15yrs)	13.0	8.1

A blood test will provide counts of white blood cells, red blood cells and platelets. If anemia appears, further tests may determine what type it is, and whether it has a serious cause. although of that, it is possible to refer to the genetic history and physical diagnosis.^[63] These tests may also include serum ferritin, iron studies, vitamin B₁₂, genetic testing, and a bome morrow sample, if needed.^[64][65]

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, such as:

) although the tests will depend on the clinical hypothesis that is being investigated. When the diagnosis remains difficult, a bone marrow examination allows direct examination of the precursors to red cells, although is rarely used as is painful, invasive and is hence reserved for cases where severe pathology needs to be determined or excluded.^{[medical citation needed]}

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

. 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. Limitations of MCV include cases where the underlying cause is due to a combination of factors – such as iron deficiency (a cause of microcytosis) and vitamin ]

Production vs. destruction or loss

The "kinetic" approach to anemia yields arguably the most clinically relevant classification of anemia. This classification depends on evaluation of several hematological parameters, particularly the blood

] The following is a simplified schematic of this approach:^[medical citation needed]

Anemia

Reticulocyte production index shows inadequate production response to anemia.

Reticulocyte production index shows appropriate response to anemia = ongoing hemolysis or blood loss without RBC production problem.

No clinical findings consistent with hemolysis or blood loss: pure disorder of production.

Clinical findings and abnormal MCV: hemolysis or loss and chronic disorder of production*.

Clinical findings and normal MCV= acute hemolysis or loss without adequate time for bone marrow production to compensate**.

Macrocytic anemia (MCV>100)

Normocytic anemia (80<MCV<100)

Microcytic anemia (MCV<80)

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

Anemia

Macrocytic anemia (MCV>100)

Normocytic anemia (MCV 80–100)

Microcytic anemia (MCV<80)

High reticulocyte count

Low reticulocyte count

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

Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies:

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 due to insufficient dietary intake or absorption of
  angular stomatitis
  ).
• In the United States, the most common cause of iron deficiency is bleeding or blood loss, usually from the gastrointestinal tract. Fecal occult blood testing, upper endoscopy and lower endoscopy should be performed to identify bleeding lesions. In older men and women, the chances are higher that bleeding from the gastrointestinal tract could be due to colon polyps or colorectal cancer.
• Worldwide, the most common cause of iron-deficiency anemia is parasitic infestation (
  amebiasis, schistosomiasis and whipworms).^[72]

The Mentzer index (mean cell volume divided by the RBC count) predicts whether microcytic anemia may be due to iron deficiency or thalassemia, although it requires confirmation.^{[73][citation needed]}

Macrocytic

• folic acid, or both.^[74] Deficiency in folate 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.
  • autoimmune condition targeting the parietal cells
    (atrophic gastritis) that produce intrinsic factor or against intrinsic factor itself. These lead to poor absorption of vitamin B₁₂.
  • Macrocytic anemia can also be caused by the removal of the functional portion of the stomach, such as during
    gastric bypass
    surgery, leading to reduced vitamin B₁₂/folate absorption. Therefore, one must always be aware of anemia following this procedure.
• Hypothyroidism
• Alcoholism commonly causes a macrocytosis, although not specifically anemia. Other types of liver disease can also cause macrocytosis.
• Drugs such as methotrexate, zidovudine, and other substances may inhibit DNA replication such as heavy metals

Macrocytic anemia can be further divided into "megaloblastic anemia" or "nonmegaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which results in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (six to 10 lobes). The nonmegaloblastic macrocytic anemias have different etiologies (i.e. unimpaired DNA globin synthesis,) which occur, for example, in alcoholism. In addition to the nonspecific symptoms of anemia, specific features of vitamin B₁₂ deficiency include

. The treatment for vitamin B₁₂-deficient anemia was first devised by

Normocytic

Normocytic anemia occurs when the overall hemoglobin levels are decreased, but the red blood cell size (mean corpuscular volume) remains normal. Causes include:

Dimorphic

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.^{[citation needed]}

Heinz body anemia

or may be caused by eating various plants or other substances:

• In cats and dogs after eating either raw or cooked plants from the genus Allium, for example, onions or garlic.^[78]
• In dogs after ingestion of zinc, for example, after eating U.S. pennies minted after 1982.^[77]
• In horses which eat dry or wilted red maple leaves.^[79]

Hyperanemia

Hyperanemia is a severe form of anemia, in which the hematocrit is below 10%.^[80]

Refractory anemia

Refractory anemia, an anemia which does not respond to

. ^[83]

Transfusion dependent

Transfusion dependent anemia is a form of anemia where ongoing blood transfusion are required.^[84] Most people with myelodysplastic syndrome develop this state at some point in time.^[85] Beta thalassemia may also result in transfusion dependence.^[86][87] Concerns from repeated blood transfusions include iron overload.^[85] This iron overload may require chelation therapy.^[88]

Treatment

The global market for anemia treatments is estimated at more than USD 23 billion per year and is fast growing because of the rising prevalence and awareness of anemia. The types of anemia treated with drugs are

Oral iron

Nutritional iron deficiency is common in developing nations. An estimated two-thirds of children and of women of childbearing age in most developing nations are estimated to have iron deficiency without anemia; one-third of them have iron deficiency with anemia.[89] Iron deficiency due to inadequate dietary iron intake is rare in men and postmenopausal women. The diagnosis of iron deficiency mandates a search for potential sources of blood loss, such as gastrointestinal bleeding from ulcers or colon cancer.^{[citation needed]}

Mild to moderate iron-deficiency anemia is treated by oral iron supplementation with

In the anemia of chronic kidney disease,

Injectable iron

In cases where oral iron has either proven ineffective, would be too slow (for example, pre-operatively), or where absorption is impeded (for example in cases of inflammation),

Blood transfusions

Blood transfusions in those without symptoms is not recommended until the hemoglobin is below 60 to 80 g/L (6 to 8 g/dL).[1] In those with coronary artery disease who are not actively bleeding transfusions are only recommended when the hemoglobin is below 70 to 80g/L (7 to 8 g/dL).^[10] Transfusing earlier does not improve survival.^[95] Transfusions otherwise should only be undertaken in cases of cardiovascular instability.^[96]

A 2012 review concluded that when considering blood transfusions for anaemia in people with advanced cancer who have fatigue and breathlessness (not related to cancer treatment or haemorrhage), consideration should be given to whether there are alternative strategies can be tried before a blood transfusion.^[97]

Vitamin B₁₂ intramuscular injections

In many cases, vitamin B₁₂ is used by intramuscular injection in severe cases or cases of malabsorption of dietary-B₁₂. Pernicious anemia caused by loss of intrinsic factor cannot be prevented.^[98] If there are other, reversible causes of low vitamin B₁₂ levels, the cause must be treated.^[99]

Vitamin B₁₂ deficiency anemia is usually easily treated by providing the necessary level of vitamin B₁₂ supplementation.^[100] The injections are quick-acting, and symptoms usually go away within one to two weeks.^[100] As the condition improves, doses are reduced to weeks and then can be given monthly. Intramuscular therapy leads to more rapid improvement and should be considered in patients with severe deficiency or severe neurologic symptoms.^[100] Treatment should begin rapidly for severe neurological symptoms, as some changes can become permanent.^[101] In some individuals lifelong treatment may be needed.^[101]

Erythropoiesis-stimulating agents

The objective for the administration of an

]

Hyperbaric oxygen

Treatment of exceptional blood loss (anemia) is recognized as an indication for

Preoperative anemia

An estimated 30% of adults who require non-cardiac surgery have anemia.[108] In order to determine an appropriate preoperative treatment, it is suggested that the cause of anemia be first determined.^[109] There is moderate level medical evidence that supports a combination of iron supplementation and erythropoietin treatment to help reduce the requirement for red blood cell transfusions after surgery in those who have preoperative anemia.^[108]

Epidemiology

Anemia affects 27% of the world's population with iron-deficiency anemia accounting for more than 60% of it.^[110] A moderate degree of iron-deficiency anemia affected approximately 610 million people worldwide or 8.8% of the population.^[13] It is somewhat more common in females (9.9%) than males (7.8%).^[13] Mild iron-deficiency anemia affects another 375 million.^[13] Severe anaemia is prevalent globally, and especially in sub-Saharan Africa^[111] where it is associated with infections including malaria and invasive bacterial infections.^[112]

History

This section needs expansion. You can help by adding to it. (August 2020)

Signs of severe anemia in human bones from 4000 years ago have been uncovered in Thailand.^[113]

References

External links

Look up anemia in Wiktionary, the free dictionary.

• WHO fact sheet on anaemia
• Anemia, U.S. National Library of Medicine

[About Anemia]