Anemia is a blood condition defined by a lack of healthy red blood cells. It is very common, having a global prevalence of 27%. Anemia affects about three million Americans and is the most common blood disorder in the United States.

A basic blood test and physical exam findings make anemia easy to diagnose. Answering why the anemia has developed, however, can be more complex.

This is the first article in an anemia series. In this article, we will explain red blood cells and anemia and briefly touch on seven types of anemia that should be included in an anemia differential. Future articles will deep dive into functional testing and treatment considerations for each type of anemia covered below.

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What is Anemia

To best understand anemia, let's first discuss the structure and function of red blood cells. Red blood cells (RBCs) are flat discs with a central indentation (giving them a doughnut-like appearance) made in the bone marrow. RBCs take about seven days to fully mature in the blood marrow and have a lifespan of about 120 days once released into the bloodstream. Each RBC contains hemoglobin, an iron-containing molecule consisting of four protein chains. In addition to giving them their shape and color, hemoglobin allows RBCs to transport oxygen and carbon dioxide through the body.

The primary function of RBCs is oxygen transportation from the lungs to the body's peripheral tissues. They then return carbon dioxide, a cellular waste product, to the lungs to be exhaled from the body. Anemia is defined by decreased circulating RBCs and/or decreased hemoglobin concentration. The general symptoms of anemia, such as fatigue and muscle weakness, reflect reduced oxygen flow to the body's vital organs.

The three leading causes of anemia include decreased red blood cell production, excessive red blood cell destruction, and blood loss. (7)

The appearance of red blood cells classifies anemia:

• Macrocytic Anemia: RBCs are larger than normal
• Microcytic Anemia: RBCs are small and often lacking in red color (hypochromic)
• Normocytic Anemia: Anemia is present without change to the size or shape of RBCs

What is Iron Deficiency Anemia?

Iron deficiency is the most common nutritional deficiency in the United States and the most common cause of anemia (2). One of iron's many critical roles in the human body is its involvement in hemoglobin synthesis. When the body lacks iron, hemoglobin synthesis is compromised, and iron deficiency anemia (IDA) develops in three stages:

1. Iron Depletion: Circulating iron is low, so the body pulls iron out of its stored form, ferritin, to compensate. Labs reveal slightly decreased ferritin with normal serum iron, RBCs, and hemoglobin.
2. Latent Iron Deficiency: Iron stores are depleted, and the body must synthesize hemoglobin and RBCs in an iron-deficient state. Labs support iron deficiency with a dwindling hemoglobin concentration and smaller RBCs.
3. Iron Deficiency Anemia: Frank anemia and associated symptoms are present. Lab findings reflect microcytic anemia with iron deficiency.

What Causes Iron Deficiency Anemia

Fetal development and increased blood volume during pregnancy, and lactation during the postpartum period, require increased daily dietary intake of iron. Without iron supplementation, IDA is very common in pregnant and breastfeeding women (2).

Consuming too little iron through diet can lead to IDA over time (2). Vegetarian, vegan, and other restricted diets (e.g., long-term elimination diets and disordered eating habits) will put a person at higher risk for IDA. Insufficient dietary intake of iron is the most common cause of IDA in young children.

Iron is absorbed into the bloodstream from the small intestine. Even if you are eating an iron-rich diet, conditions predisposing you to iron malabsorption can lead to IDA (1, 2). These may include:

• Celiac disease
• Crohn's disease
• Helicobacter pylori infection
• Hypochlorhydria
• Small intestinal bacterial overgrowth (SIBO)

Finally, the body loses iron through bleeding. The most common cause

of IDA in menstruating adults is menstrual blood loss due to heavy periods. Gastrointestinal pathologies - such as ulcers, hemorrhoids, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), and certain cancers - can cause chronic blood loss and particularly need to be ruled out in adult males and non-menstruating females with unexplained IDA. Frequent blood donations can also lead to iron deficiency and IDA. (1, 2)

What is B12 Deficiency Anemia

Vitamin B12 deficiency anemia is one of the leading causes of megaloblastic anemia, a type of macrocytic anemia (3). When the body has insufficient vitamin B12, DNA synthesis is impaired, and large, abnormal RBCs, called megaloblasts, develop in the bone marrow. Slowed RBC production and the shortened lifespan of megaloblasts contribute to anemia.

What Causes B12 Deficiency Anemia

The most frequent cause of vitamin B12 deficiency is pernicious anemia, caused by the inability to absorb vitamin B12 due to decreased intrinsic factor (IF). To be absorbed from the small intestine into the bloodstream, vitamin B12 must be bound to IF, produced by the stomach's parietal cells. Atrophic gastritis (chronic stomach inflammation leading to a weakened stomach lining), autoimmunity against IF, and autoimmunity against parietal cells may cause pernicious anemia. (4, 5)

Other causes of vitamin B12 deficiency secondary to malabsorption include surgical removal of the stomach and small intestine, SIBO, Celiac disease, Crohn's disease, exocrine pancreatic insufficiency (EPI), and Helicobacter pylori infection (4). Excess alcohol consumption can also impair B12 absorption.

Animal foods like meats, fish, eggs, and dairy are natural sources of vitamin B12. Therefore, vegetarians and vegans are at higher risk for B12 deficiency.

Medications known to cause vitamin B12 deficiency include proton pump inhibitors (PPIs) and histamine H2 antagonists used to treat heartburn, oral contraceptives for birth control, and metformin commonly used to treat type II diabetes mellitus (10).

What is Folate Deficiency Anemia

Folate deficiency is another leading cause of megaloblastic anemia. Folate is another B vitamin required for DNA synthesis and cell division; with insufficient levels, the bone marrow produces fewer megaloblastic cells with short lifespans. (3)

What Causes Folate-Deficiency Anemia

Frank folate deficiency is rare in the United States, but some groups are at higher risk for suboptimal and deficient folate status.

Alcohol use disorder is associated with poor quality and folate-deficient diets. Alcohol further increases the risk of folate deficiency by interfering with folate absorption and increasing its excretion from the body. (6)

Because of its role in DNA synthesis and fetal development, demands for folate increase from 400 mcg dietary folate equivalents (DFE) daily to 600 mcg DFE and 500 mcg DFE daily during pregnancy and lactation, respectively. Pregnant and lactating women are at higher risk for folate deficiency, especially if they are not taking supplemental folic acid. (6)

Gastrointestinal malabsorptive disorders (i.e., Celiac disease and inflammatory bowel disease) and conditions characterized by diminished stomach acid secretions (i.e., atrophic gastritis and hypochlorhydria) increase the risk of folate deficiency. (6)

Medications that can deplete folate levels include (10):

• Acid-reducing medications for heartburn: PPIs, histamine H2 antagonists, antacids
• Antipsychotic medications
• Oral contraceptives
• Anticonvulsant medications used to treat epilepsy (6)
• Methotrexate, used to treat certain cancers and autoimmune diseases (6)
• Metformin

What is Aplastic Anemia

Aplastic anemia is a serious inherited or acquired blood disorder resulting from the bone marrow's inability to make enough new blood cells. Damage to stem cells within the bone marrow inhibits the production of RBCs, white blood cells, and platelets.

What Causes Aplastic Anemia

Aplastic anemia is rare but may be caused by the following:

• Autoimmune disease: the most common cause of aplastic anemia is the immune system's attack against healthy bone marrow, which destroys stem cells (7)
• Exposure to toxic environmental chemicals, such as pesticides, insecticides, arsenic, and benzene
• Cancer treatment with high-dose radiation and chemotherapy (7)
• Certain medications, such as chloramphenicol (an antibiotic) and gold compounds (used to treat rheumatoid arthritis) (7)
• Viral infections associated with the development of aplastic anemia include hepatitis viruses, Epstein Barr, cytomegalovirus, parvovirus B19, and HIV.
• Inherited disorders such as Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, and Diamond-Blackfan anemia

What is Thalassemia

Thalassemia is an inherited blood disorder in which the body does not make enough hemoglobin, preventing adequate production of healthy RBCs. There are two types of thalassemia: alpha-thalassemia and beta-thalassemia.

The normal molecular structure of hemoglobin in adults consists of four protein chains: two alpha chains and two beta chains. Genetic mutations decrease the synthesis of the alpha- or beta-protein chains, resulting in microcytic anemia with hemoglobin deficiency. Symptom severity varies depending on the form of thalassemia present.

Alpha-Thalassemia

Four genes are involved in the synthesis of the alpha-hemoglobin chain. The severity of alpha-thalassemia is dependent on the number of gene mutations present:

• One gene mutation: the individual will not present with signs or symptoms of thalassemia but may pass the disease to their children
• Two gene mutations: mild anemia present
• Three gene mutations: moderate-to-severe anemia present
• Four gene mutations: rare, and results in a nonviable pregnancy

Beta-Thalassemia

Two genes are involved in the synthesis of the beta-hemoglobin chain:

• Thalassemia Minor results from one gene mutation and usually presents as mild anemia on lab work without symptoms
• Thalassemia Major results from two gene mutations. Babies are healthy at birth, but severe anemia and associated symptoms appear within the first two years of life.

What Causes Thalassemia

Mutated hemoglobin genes are inherited from your parents, as described above, and dictate the form and severity of thalassemia present.

Factors that increase the risk of thalassemia include (7):

• Family history of thalassemia
• Ancestry: thalassemia most commonly occurs in people of African, Mediterranean, and Southeast Asian descent

What is Sickle Cell Anemia

Sickle cell anemia is a manifestation of sickle cell disease (SCD), an inherited condition caused by genetic mutations in the beta-hemoglobin gene. SCD results in the production of sickle, or crescent, shaped RBCs that are "sticky" and only live for 10-20 days. Increased destruction, or hemolysis, of the abnormal RBCs leads to anemia. The irregular shape of the RBCs also predisposes people with SCD to many other cardiovascular complications.

What Causes Sickle Cell Anemia

To have SCD, a person must inherit two abnormal beta-hemoglobin genes, one from each parent.

Sickle cell trait is the inheritance of just one abnormal beta-hemoglobin gene. People with sickle cell trait are usually asymptomatic without any signs of disease. They can pass on the abnormal gene to their children.

People of African, Hispanic, Mediterranean, and Middle Eastern descent are at the highest risk of inheriting SCD.

What is Anemia of Chronic Disease

Anemia of chronic disease (ACD) is an anemia that affects people with concurrent inflammatory conditions. This anemia results from a lack of red blood cell production secondary to inflammation. It can present as either a microcytic or normocytic anemia. Anemia of chronic disease is the second most common type of anemia worldwide. (8)

What Causes Anemia of Chronic Disease

Three underlying mechanisms have been identified in the pathology behind anemia of chronic disease (8, 9):

• Shortened RBC lifespan
• Increased production of proteins called acute phase reactants from the liver, including hepcidin. Hepcidin sequesters iron in storage sites and inhibits normal iron recycling.
• Suppression of erythropoietin, the hormone that stimulates RBC production

Conditions associated with anemia of chronic disease include:

• Autoimmune disease
• Cancer
• Chronic infection
• Chronic kidney disease
• Congestive heart failure
• Obesity

Summary

Anemia is a prevalent blood disorder defined by low red blood cells and hemoglobin concentration, leading to poor oxygenation and related symptoms. Anemia has many underlying causes; an accurate diagnosis is the first step in successfully treating anemia. This article serves to help create a differential diagnosis for anemia discovered in lab findings. Sequential articles in this anemia series will detail classic laboratory and physical exam findings for each of the anemias discussed above and will outline anemia-specific recommendations to be considered in a functional medicine treatment approach.