Anemia is a major but treatable global health problem

Stefan Lindgren, Sweden and Maria Cappellini, Italy

Anemia is the result of a decrease in the level of hemoglobin and too few circulating red blood cells, resulting in poor oxygen delivery to tissues and organs in the body. Anemia may therefore lead to lack of physical and mental capacity, tiredness, loss of breath during physical effort and several other symptoms. In addition, the reason behind anemia may cause additional symptoms from various organ systems.

Anemia is a major global health problem with severe consequences for millions of people, particularly young and pregnant women. Moreover, anemia in the elderly though often mild, is quite common and independently associated with important clinical outcomes including decreased quality of life, risk of falls and fractures, cognitive decline, increased length of hospital stay and even mortality. It is often difficult to dissect the cause(s) of anemia in the elderly which is typically multifactorial and a limited diagnostic approach often leads to categorization of the anemia as “unexplained”.

The principal mechanisms behind anemia are failure to produce red blood cells due to diseases in the bone marrow, lack of essential components of hemoglobin such as iron, folic acid and vitamin B 12, shorter survival of red blood cells than the normal 120 days, drug treatment or inherited abnormalities of the hemoglobin molecule.

The degree of anemia is evaluated by measuring the concentration of hemoglobin in blood, presented as hemoglobin concentration in grams per liter blood. According to the World Health Organization (WHO), the lower normal level of hemoglobin is 130 g/L (8.1 mmol/L) in men and 120 g/L (7.5 mmol/L) in non – pregnant women. However, this represents lower normal levels and actual normal levels in healthy women and men are rather narrower – 140 – 150 g/L (8.7 – 9,3 mmol/L).

Iron deficiency
The far most common cause of anemia is iron deficiency. The absorption of iron from oral intake is rather small, and increased losses of iron through chronic bleeding therefore rapidly leads to lack of body iron, and consequently anemia. Such bleedings may occur due to menstruation, or from diseases in the gastrointestinal tract or female genital organs. Diets lacking adequate amounts of iron may also cause iron deficiency anemia. Another reason for iron deficiency is systemic inflammation in the body leading to blocking of absorption of iron from the bowel and retention of iron in the body stores.

Normally the body in an adult contains approximately 4 grams of iron, most of which is found in circulating red blood cells, and in various stores such as the liver. The level of these stores can be estimated by measuring ferritin in the blood. When the supply of iron is inadequate, firstly the iron stores run empty and secondly the production of new red blood cells from the bone marrow fails. The diagnosis of iron deficiency and iron deficiency anemia is thus based on analysis of hemoglobin, ferritin and transport of iron in the blood by transferrin (percentage of transferrin saturation). In case of inflammation ferritin is not a reliable marker, so that the estimation of iron availability must be related to the degree of inflammation.

Symptoms in individuals with iron deficiency are related to the degree of anemia but also to consequences of insufficient function of several energy-generating and energy-dependent processes in the body where iron plays a major role. It is thus not surprising that individuals with iron deficiency, even in the absence of anemia, may suffer from fatigue, lack of concentration and mental energy, worsening of heart failure and muscular weakness. Treatment of iron deficiency with iron supplements is preferably given by mouth when the bowel system is healthy and when there is no systemic inflammation. However, it takes several, up to 6 months, of treatment to restitute the hemoglobin levels and refill the iron stores. However, oral iron tablets may give gastrointestinal side-effects, and follow up to reassure that the goals of treatment, normalization of hemoglobin levels and replacement of iron stores, are met is essential. If oral treatment fails or is insufficient, intravenous iron infusions offer quick and safe restitution of even big iron deficiencies.

Other causes of anemia
Other acquired forms of anemia include immune-mediated destruction of red blood cells (hemolysis) or of immature forms in the bone-marrow (aplastic anemia). The rarity of these diseases along with clinical and laboratory overlaps may result in misdiagnosis and delays in proper treatment.

Anemia can also be inherited due to different mechanisms: (1) defects in globin chains (hemoglobinopathies or thalassemias). (2) defects in heme synthesis and (3) defects in iron availability of hemoglobin components (globin, iron and heme) that in turn causes a reduced hemoglobin content in immature red cells and delayed maturation. Rare forms of anemia often remain misdiagnosed and treatment options have been limited to supportive care, mainly blood transfusions.

During the last decades the elucidation of molecular mechanisms has paved the way for allogenic bone marrow transplantation or specific antibodies targeting different steps of the complex disease mechanisms. Gene therapy represents an innovative and encouraging strategy currently under evaluation in several forms of rare anemias and is recently approved for beta-thalassemia. Moreover, the advancements in gene-editing technologies represent an additional option focused on correcting the defective gene.

Conclusions
Anemia is a major global health problem. Awareness of anemia and correct diagnosis, including the cause of anemia, is a prerequisite for adequate treatment. The treatment options today are excellent and have the potential to improve both survival, function, and quality of life of patients with anemia.