Anemia

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Anemia
Other namesAnaemia, erythrocytopenia
Iron deficiency anemia blood film.jpg
Blood smear showing iron-deficiency anemia, with small, pale red blood cells
Pronunciation
Specialty Hematology
Symptoms Feeling tired, pale skin, weakness, shortness of breath, feeling faint [1]
Causes Blood loss, decreased red blood cell production, increased red blood cell breakdown [1]
Diagnostic method Blood hemoglobin measurement [1]
Frequency1.92 billion / 24% (2021) [2]

Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin available for oxygen transport, or abnormalities in hemoglobin that impair its function. [3] [4] The name is derived from Ancient Greek ἀν- (an-) 'not'andαἷμα (haima) 'blood'. [5]

Contents

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 blood loss, decreased red blood cell production, and increased red blood cell breakdown. [1] Causes of blood loss include Menstruation,bleeding due to inflammation of the stomach or intestines, bleeding from surgery, serious injury, or blood donation. [1] Causes of decreased production include iron deficiency, folate deficiency, vitamin B12 deficiency, thalassemia and a number of bone marrow tumors. [1] Causes of increased breakdown include genetic disorders such as sickle cell anemia, infections such as malaria, and certain autoimmune diseases like autoimmune hemolytic anemia. [1]

Anemia can also be classified based on the size of the red blood cells and amount of hemoglobin in each cell. [1] If the cells are small, it is called microcytic anemia; if they are large, it is called macrocytic anemia; and if they are normal sized, it is called normocytic anemia. [1] The diagnosis of anemia in men is based on a hemoglobin of less than 130 to 140 g/L (13 to 14 g/dL); in women, it is less than 120 to 130 g/L (12 to 13 g/dL). [1] [7] Further testing is then required to determine the cause. [1] [8]

Treatment depends on the specific cause. Certain groups of individuals, such as pregnant women, can benefit from the use of iron pills for prevention. [1] [9] Dietary supplementation, without determining the specific cause, is not recommended. [1] The use of blood transfusions is typically based on a person's signs and symptoms. [1] In those without symptoms, they are not recommended unless hemoglobin levels are less than 60 to 80 g/L (6 to 8 g/dL). [1] [10] These recommendations may also apply to some people with acute bleeding. [1] Erythropoiesis-stimulating agents are only recommended in those with severe anemia. [10]

Anemia is the most common blood disorder, affecting about a fifth to a third of the global population. [1] [11] [12] [13] Iron-deficiency anemia is the most common cause of anemia worldwide, and affects nearly one billion people. [14] In 2013, anemia due to iron deficiency resulted in about 183,000 deaths – down from 213,000 deaths in 1990. [15] This condition is most prevalent in children [16] [17] with also an above average prevalence in elderly [1] and women of reproductive age (especially during pregnancy). [14] Anemia is one of the six WHO global nutrition targets for 2025 and for diet-related global targets endorsed by World Health Assembly in 2012 and 2013. Efforts to reach global targets contribute to reaching Sustainable Development Goals (SDGs), [18] with anemia as one of the targets in SDG 2 for achieving zero world hunger. [19]

Signs and symptoms

Main symptoms that may appear in anemia Symptoms of anemia.png
Main symptoms that may appear in anemia
The hand of a person with severe anemia (on the left, with ring) compared to one without (on the right) Anemia.JPG
The hand of a person with severe anemia (on the left, with ring) compared to one without (on the right)

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. [21] 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. [22]

Symptoms of anemia are written in Bengali, Hindi and English language on a board at AIIMS Kalyani, West Bengal. Symptoms of anemia are written in Bengali, Hindi and English language on a board at AIIMS Kalyani - 1.jpg
Symptoms of anemia are written in Bengali, Hindi and English language on a board at AIIMS Kalyani, West Bengal.

Symptoms of anemia can come on quickly or slowly. [23] Early on there may be few or no symptoms. [23] If the anemia continues slowly (chronic), the body may adapt and compensate for this change. In this case, no symptoms may appear until the anemia becomes more severe. [20] [24] Symptoms can include feeling tired, weak, dizziness, headaches, intolerance to physical exertion, shortness of breath, difficulty concentrating, irregular or rapid heartbeat, cold hands and feet, cold intolerance, pale or yellow skin, poor appetite, easy bruising and bleeding, and muscle weakness. [23]

Anemia that develops quickly, often, has more severe symptoms, including, feeling faint, chest pain, sweating, increased thirst, and confusion. [23] [25] [26] [27] There may be also additional symptoms depending on the underlying cause. [1]

In more severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The person 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. [28]

On examination, the signs exhibited may include pallor (pale skin, mucosa, conjunctiva, and nail beds), but this is not a reliable sign.

Iron-deficiency anemia may give symptoms that can include spoon-shaped nails, restless legs syndrome, and pica (the desire to eat things which are not food, such as ice, dirt, etc.). [29] A blue coloration of the sclera may be noticed in some cases of iron-deficiency anemia. [30] Vitamin B12 deficiency anemia may result in decreased ability to think, memory loss, confusion, personality or mood changes, depression, difficulty walking, blurred vision, and irreversible nerve damage. [31] [32] Other specific causes of anemia may have signs and/or complications such as, jaundice with the rapid break down of red blood cells as with hemolytic anemia, bone abnormalities with thalassemia major, or leg ulcers as 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, paper, wax, grass, hair or dirt, may be a symptom of iron deficiency; [29] 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. [33]

Causes

Figure shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin. Modified sickle cell 01.jpg
Figure shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin.

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

Chronic inflammation can disrupt iron handling limiting its availability for red blood cell formation. During inflammatory states, the liver produces high levels of hepcidin, a hormone that blocks iron release from intestinal cells and macrophages. This leads to high ferritin levels and low transferrin saturation, a pattern known as "functional iron deficiency." This mechanism is commonly seen in older hospitalized patients with long-standing illnesses such as infections, heart failure or autoimmune conditions. [37]

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. [40] [41]

Blood loss

The roots of the words anemia and ischemia both refer to the basic idea of "lack of blood", but anemia and ischemia are not the same thing in modern medical terminology. The word anemia used alone implies widespread effects from blood that either is too scarce (e.g., blood loss) or is dysfunctional in its oxygen-supplying ability (due to whatever type of hemoglobin or erythrocyte problem). In contrast, the word ischemia refers solely to the lack of blood (poor perfusion). Thus, ischemia in a body part can cause localized anemic effects within those tissues. [52]

Fluid overload

Fluid overload (hypervolemia) causes decreased hemoglobin concentration and apparent anemia: [53]

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. [56] [57] [58] Chronic intestinal inflammation increases hepcidin activity, which restricts iron release from storage sites. This mechanism limits iron availability even when total body iron stores are adequate, contributing to anemia common in inflammatory bowel diseases and chronic infections. [39]

Diagnosis

Peripheral blood smear microscopy of a patient with iron-deficiency anemia Iron deficiency anemia.jpg
Peripheral blood smear microscopy of a patient with iron-deficiency anemia
A Giemsa-stained blood film from a person with iron-deficiency anemia. This person also had hemoglobin Kenya. Fe- deficient anemia.jpg
A Giemsa-stained blood film from a person with iron-deficiency anemia. This person also had hemoglobin Kenya.

Definitions

There are several definitions of anemia; reviews provide a comparison and contrast of them. [64] A strict but broad definition is an absolute decrease in red blood cell mass, [65] however, a broader definition is a lowered ability of the blood to carry oxygen. [66] 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. [67]

It is difficult to directly measure RBC mass, [68] so the hematocrit (amount of RBCs) or the hemoglobin (Hb) in the blood are often used instead to indirectly estimate the value. [69] 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 remain 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. [70] Different values are used in pregnancy and children. [70]

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 [71] (1 g/dL = 0.6206 mmol/L)
Age or gender groupHb threshold (g/dL)Hb threshold (mmol/L)
Children (0.5–5.0 yrs)11.06.8
Children (5–12 yrs)11.57.1
Teens (12–15 yrs)12.07.4
Women, non-pregnant (>15yrs)12.07.4
Women, pregnant11.06.8
Men (>15yrs)13.08.1

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. [72] These tests may also include serum ferritin, iron studies, vitamin B12, genetic testing, and a bone marrow sample, if needed. [73] [74]

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 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 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: ESR, serum iron, transferrin, RBC folate level, hemoglobin electrophoresis, renal function tests (e.g. serum creatinine) 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 it is rarely used as it 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 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. 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 B12 deficiency (a cause of macrocytosis), where the net result can be normocytic cells.[ medical citation needed ]

Production vs. destruction or loss

The "kinetic" approach to anemia yields arguably the most clinically relevant classification of anemia. This classification depends on the 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 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 guaiac-positive stool, radiographic findings, or frank bleeding.[ medical citation needed ] 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 countLow 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 iron to meet the body's needs. Infants, toddlers, and pregnant women have higher-than-average needs. Increased iron intake is also needed to offset blood losses due to digestive tract issues, frequent blood donations, or heavy menstrual periods. [76] 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, 12% of all women of childbearing age have iron deficiency, compared with only 2% of adult men. The incidence is as high as 20% among African American and Mexican American women. [77] In India it is even more than 50%. [78] Studies have linked iron deficiency without anemia to poor school performance and lower IQ in teenage girls, although this may be due to socioeconomic factors. [79] [80] Iron deficiency is the most prevalent deficiency state on a worldwide basis. It is sometimes the cause of abnormal fissuring of the angular (corner) sections of the lips (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 (hookworms, amebiasis, schistosomiasis and whipworms). [81]

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. [82] [ citation needed ]

Macrocytic

  • Megaloblastic anemia, the most common cause of macrocytic anemia, is due to a deficiency of either vitamin B12, folic acid, or both. [83] 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.
    • Pernicious anemia is caused by a lack of intrinsic factor, which is required to absorb vitamin B12 from food. A lack of intrinsic factor may arise from an 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, with excessive alcohol use. In addition to the nonspecific 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. [84] Other features may include a smooth, red tongue and 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 isolate the curative substance chemically and ultimately were able to isolate the vitamin B12 from the liver. All three shared the 1934 Nobel Prize in Medicine. [85]

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

Heinz bodies form in the cytoplasm of RBCs and appear as small dark dots under the microscope. In animals, Heinz body anemia has many causes. It may be drug-induced, for example, in cats and dogs by acetaminophen (paracetamol), [86] 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. [87]
  • In dogs after ingestion of zinc, for example, after eating U.S. pennies minted after 1982. [86]
  • In horses which eat dry or wilted red maple leaves. [88]

Hyperanemia

Hyperanemia is a severe form of anemia, in which the hematocrit is below 10%. [89]

Refractory anemia

Refractory anemia, an anemia which does not respond to treatment, [90] is often seen secondary to myelodysplastic syndromes. [91] Iron-deficiency anemia may also be refractory as a manifestation of gastrointestinal problems which disrupt iron absorption or cause occult bleeding. [92]

Transfusion dependent

Transfusion-dependent anemia is a form of anemia where ongoing blood transfusions are required. [93] Most people with myelodysplastic syndrome develop this state at some point in time. [94] Beta thalassemia may also result in transfusion dependence. [95] [96] Concerns from repeated blood transfusions include iron overload. [94] This iron overload may require chelation therapy. [97]

Treatment

The global market for anemia treatments is estimated at more than USD 23 billion per year and is growing rapidly because of the rising prevalence and awareness of anemia. [13] In order to treat anemia, the underlying cause and its severity would first need to be identified [6] . Different causes and types of anemia mean there are different treatments. Drugs, for example, are used to treat iron-deficiency anemia, thalassemia, aplastic anemia, hemolytic anemia, sickle cell anemia, and pernicious anemia, with iron-deficiency and sickle cell anemia taking up 60% of market share due to having the highest prevalence as well as highest treatment costs. [13]

More specifically, iron supplements, antibiotics, immunosuppressants, bone marrow stimulants, corticosteroids, gene therapy, and iron chelating agents are forms of anemia treatment drugs, with immunosuppressants and corticosteroids accounting for 58% of the market share. [13] A paradigm shift towards gene therapy and monoclonal antibody therapies is observed. [13] Besides drugs, treatments include replenishing specific deficiencies that may be causing anemia. [6] Vitamin supplements given orally (folic acid or vitamin B12) or intramuscularly (vitamin B12) to replace specific deficiencies. [1] More invasive treatments include blood transfusions, blood or bone marrow transplantation, or even surgery. [4] Otherwise, oxygen may be given, and a dietary change is suggested. [6]

Oral Iron

Iron deficiency results in the decreased production of hemoglobin, the oxygen-carrying protein in red blood cells. [98] In developing nations, an estimated two-thirds of children and women of childbearing age (15-49) are estimated to have iron deficiency without anemia, with one-third of them having an iron deficiency with anemia. [99] Child-bearing women may not have access to certain medications or appropriate nutrition due to socioeconomic factors, which may affect the chances for developing anemia. [100] Iron deficiency due to inadequate dietary iron intake is rare in men and postmenopausal women. In some cases, the diagnosis of iron deficiency mandates a search for potential sources of blood loss, such as gastrointestinal bleeding from ulcers or colon cancer. [99]

Mild to moderate iron-deficiency anemia is treated by oral iron supplementation with ferrous sulfate, ferrous fumarate, or ferrous gluconate. [98] Daily iron supplements are effective in reducing anemia in women of childbearing age. [101] Because these iron supplements are taken orally, gastrointestinal side effects, including stomach upset, vomiting, or darkening of the feces, are commonly experienced. [98] The stomach upset can be alleviated by taking the iron with food; however, this decreases the amount of iron absorbed. Vitamin C aids in the body's ability to absorb iron, so taking oral iron supplements with orange juice is of benefit. [102]

In the anemia of chronic kidney disease, recombinant erythropoietin or epoetin alfa is recommended to stimulate RBC production, and if iron deficiency and inflammation are also present, concurrent parenteral iron is also recommended. [103]

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), parenteral iron preparations can be used. Parenteral iron can improve iron stores rapidly and is also effective for treating people with postpartum haemorrhage, inflammatory bowel disease, and chronic heart failure. [104] The body can absorb up to 6 mg iron daily from the gastrointestinal tract. In many cases, the patient has a deficit of over 1,000 mg of iron, which would require several months to replace. This can be given concurrently with erythropoietin to ensure sufficient iron for increased rates of erythropoiesis. [105]

Injectable iron (iron supplement) is available both intravenously and intramuscularly, with IV treatment more common than IM as IM may have inconsistent absorption. Possible side effects of IV iron supplementation include infusion reactions and anaphylaxis, depending on the patient's conditions. Possible side effects of IM iron supplementation include site injection pain and stained skin. [98] Before an individual is given any iron supplements, an extensive workup is performed by a primary healthcare provider. Too much iron can be damaging, and intake is monitored. [98]

Blood Transfusions

Blood transfusions work to replace blood lost in surgery, injury, or to make up for the blood the body isn't producing. More blood means more hemoglobin and oxygen being carried throughout the body. In this treatment, healthy blood, often voluntarily donated, is provided through an IV line connected to the blood vessels. The healthy blood, before being given, is carefully tested and handled, and further tests are conducted to confirm a match with the patient. [106]

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. [107] Transfusions otherwise should only be undertaken in cases of cardiovascular instability. [108]

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 that can be tried before a blood transfusion. [109]

A blood transfusion is not without risk. During a blood transfusion, the patient is monitored during and after for any side effects. Even if the donor blood is tested, handled, and matched correctly, patients can still experience reactions ranging from mild (fevers) to severe (alloimmunization). Otherwise, there is a chance of getting too much iron from extensive transfusions and a very slim chance of getting an infectious disease (extensive testing is done). [106]

Bone Marrow Transplant

Bone Marrow is the site for new red blood cell production, and if the bone marrow is unable to produce enough red blood cells, a transplant could be recommended. Aplastic anemia, for example, is the result of bone marrow failing to produce red blood cells. [110] In a bone marrow transplant, old defective bone marrow is destroyed using drugs or radiation and replaced with new stem cells. Before the transplant, like a blood transplant, the bone marrow must be carefully tested and must be compatible. Sometimes, the stem cells can come from the patient themselves (autologous), and other times, the cells will come from a donor (allogenic). The patient is monitored before, during, and after the transplant for any complications. [106]

A bone marrow transplant is an intensive therapy and comes with risks and possible complications. The treatment weakens the immune system and leaves the body weak against possible infections and bleeding, especially while the stem cells get settled and grow into bone marrow. [110] In other cases, there's the risk that the donated stem cells attack the body (graft-versus-host disease) or the patient's body rejects the donated stem cells. Additionally, the patient is likely to be put on medication that could have their own side effects, or experience side effects of the radiation and drugs used to destroy the old bone marrow. [106]

Vitamin B12 Intramuscular Injections

Pernicious anemia results from a lack of vitamin B12 absorbed. Vitamin B12 is supplemented via intramuscular injection in severe cases or cases of malabsorption of dietary-B12. Pernicious anemia caused by loss of intrinsic factor cannot be prevented. [111] If there are other, reversible causes of low vitamin B12 levels, the cause must be treated. [112]

Vitamin B12 deficiency anemia is usually easily treated by providing the necessary level of vitamin B12 supplementation. [113] The injections are quick-acting, and symptoms usually go away within one to two weeks. [113] 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. [113] Treatment should begin rapidly for severe neurological symptoms, as some changes can become permanent. [32] In some individuals lifelong treatment may be needed. [32]

Erythropoiesis-Stimulating Agents

Erythropoiesis-stimulating agents (ESA) work to increase endogenous erythropoietin (EPO) production, a hormone that increases the production of red blood cells. [114] The objective for the administration of an ESA is to maintain hemoglobin at the lowest level that both minimizes transfusions and meets the person's needs. [115] They should not be used for mild or moderate anemia. [107] They are not recommended in people with chronic kidney disease unless hemoglobin levels are less than 10 g/dL or they have symptoms of anemia. Their use should be along with parenteral iron. [115] [116]

The 2020 Cochrane Anaesthesia Review Group review of erythropoietin (EPO) plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery demonstrated that patients were much less likely to require red cell transfusion, and in those transfused, the volumes were unchanged (mean difference -0.09, 95% CI -0.23 to 0.05). Pre-operative hemoglobin concentration was increased in those receiving 'high dose' EPO, but not 'low dose'. [117]

The use of ESAs is heavily monitored by healthcare professionals as dosage and type vary among patients. A baseline for hemoglobin is set prior to treatment and continuously monitored throughout treatment. Risks involve reactions to the ESA and possible overdose if not carefully monitored. [114]

Hyperbaric Oxygen

Treatment of exceptional blood loss (anemia) is recognized as an indication for hyperbaric oxygen (HBO) by the Undersea and Hyperbaric Medical Society. [118] [119] HBO therapy involves being in a higher air pressure chamber filled with pure oxygen. Higher than normal air pressure means heavier breathing, and by supplying the room with pure oxygen, the body takes in more pure oxygen. [120]

The use of HBO is indicated when oxygen delivery to tissue is not sufficient in patients who cannot be given blood transfusions for medical or religious reasons. HBO may be used for medical reasons when the threat of blood product incompatibility or concern for transmissible disease are factors. [118] The beliefs of some religions (ex: Jehovah's Witnesses) may require they use the HBO method. [118] A 2005 review of the use of HBO in severe anemia found that all publications reported positive results. [121]

HBO does not often have lasting side effects. Any complications that arise are often mild and do not last. Ear pain or sinus pressure may arise with the higher air pressure. Serious complications, although very uncommon, can involve seizures from too much oxygen or collapsed lungs from too much pressure. As with many other treatments, the risk of complications increases the longer and the more repeats there are. [120]

Preoperative Anemia

An estimated 30% of adults who require non-cardiac surgery have anemia. [122] To determine an appropriate preoperative treatment, it is suggested that the cause of anemia be first determined. [123] 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. [122]

Epidemiology

Anemia affects 27% of the world's population, with iron-deficiency anemia accounting for more than 60% of it. [124] A moderate degree of iron-deficiency anemia affected approximately 610 million people worldwide or 8.8% of the population. [14] It is somewhat more common in females (9.9%) than males (7.8%). [14] Mild iron-deficiency anemia affects another 375 million. [14]

Anemia is most frequent in older populations, affecting up to ~17% of a cohort of individuals above the age of 65 years old. [125] In neonates (0-6 days old), hemoglobinopathies are the primary contributor to disorders related to anemia, as newborns retain their iron stores they accumulated during pregnancy. As children grow, the causes and patterns of developing anemia shift. Anemia-related disability rate is especially high among children under 5 years old, with boys experiencing slightly higher rates, potentially due to biological differences in iron metabolism. [126]

Population Groups at Higher Risk

Certain populations experience disproportionately higher rates of anemia. For example, African Americans have an elevated risk of developing anemia compared with other racial groups. [127] Severe anaemia is prevalent globally, and especially in sub-Saharan Africa [128] where it is associated with infections including malaria and invasive bacterial infections. [129] Children under 5 years old in low-income regions represent a high-risk population. In a survey of 96,804 children across 27 sub-Saharan African countries, nearly 60% were anemic (one of the highest regional burdens worldwide). Socioeconomic and maternal factors accounted for more than two-thirds of this burden, with children from crowded households or communities with inadequate sanitation facing substantially higher risk. [130] Pregnant women also carry an increased risk of developing anemia when infected with malaria. [131] Globally, the prevalence of anaemia in women aged 15 to 49 years increased from 28.5% in 2012 to 29.9% in 2019 and is projected to reach 32.3% by 2030, missing the Sustainable Development Goal target of a 50 percent reduction by 2030. [132]

History

Signs of severe anemia in human bones from 4000 years ago have been uncovered in Thailand. [133]

A cyanobacteria began producing oxygen over three billion years ago, which increased metabolic efficiency which was beneficial, but it also oxidized soluble ferrous iron into insoluble ferric iron which made it harder for living organisms to access the iron. This led to banded iron formations and forced aerobic organisms to evolve iron-acquisition strategies.The first discovery and discussion of blood was in 1674 when Antoni van Leeuwenhoek described red blood cells (RBCs) as "small round globules." RBCs counterpart, hemoglobin, wasn't discovered until much later by FL Hünefeld in 1840. In 1746, Vincenzo Menghini showed that iron was concentrated in the red blood cells using a magnetic knife [134] . Between 1877-1885, many key tools emerged like hemocytometer (RBC count), hemoglobin measurement, and hematocrit measurement that allowed for quantitative diagnosis of blood [135] . By the 1920s it was confirmed by multiple different studies that iron existed in plasma. McCance and Widdowson showed that iron is not excreted from the body in 1938, and it was later confirmed that iron absorption is the main way the body regulates iron levels. Factors that increase absorption are anemia, hypoxia, and iron depletion, while factors that decrease absorption are transfusions and iron overload.

In ancient cultures, like Assyria and Mediterranean societies, used iron for medical treatments, however, this occurred before iron's biological role was understood. In the 1500s, Nicholas Monarde used iron's "healing powers" to treat gout, acne and hair loss [134] . Anemia started out as a clinical entity in 1807. Early diagnosis of anemia in the early 1800s were based solely on physical examinations such as fatigue, paleness, sweating, difficulty breathing, and dizziness. It wasn't until late in the 1800s when new technologies allowed for a more in depth, lab-based diagnosis on anemia. Also in the 17th and 18th century, water borne parasites may have contributed to the spread of iron deficiency anemia. [136] In 1939, anemia was officially defined as "a deficiency of blood not due to hemorrhage [135] ."  The term Chlorosis or "green disease" was used in the 17th century and referred to a disease that affected mostly adolescent females with the symptoms of paleness, headaches, loss of appetite, indigestion, and exhaustion. In the late 17th century, Thomas Sydenham advocated for the use of iron as treatment for the disease. The disease mysteriously disappeared, and it was determined that it was likely due to the change in American lifestyles in the early 20th century, such as diminished prejudice or eating meat and abandonment of tight lacing/corsets. The term can not be found in any hematology textbooks, but is generally understood that chlorosis was caused by iron deficiency [134] . In today's medicine a combination of both physical examination and lab testing/results are used to diagnose a patient with anemia.

Sources

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