Anemia is a complex and varied condition characterized by low levels of erythrocytes (red blood cells) and hemoglobin. There are many types of anemia. In a recent post on B12 injections, we talked about B12 deficiency anemia. In this post we'll expand on the anemia piece and talk more about different types of anemia including iron deficiency anemia, hemolytic anemia and sickle cell anemia. We'll also delve into some of the lab markers that are used to distinguish different types of anemia.
Anemia is a large topic so we'll get to as much as we can in this post, and expand in future posts. We'll also touch on ways that anemia can interact with other conditions like Small Intestine Bacterial Overgrowth (SIBO) and chronic inflammation. In addition, we'll talk about iron and iron deficiency anemia, especially as it relates to vegan and strict vegetarian diets, which are often deficient in heme iron as well as vitamin B12. There is a lot to cover and you're bound to learn something new, like how B12 analogues from spirulina can actually block B12 absorption! Keep reading to learn more.
Definition of anemia
For a quick recap, anemia is a deficiency of erythrocytes, or red blood cells (RBCs), which transport oxygen to all the cells of the body where it is used to fuel the mitochondria. Erythropoesis, or manufacture of RBCs, takes place in the bone marrow. The RBCs are then transported to the bloodstream where they live for about 120 days in a healthy individual. Depressed hemoglobin levels can also cause anemia.
Generally speaking, most anemia has one of two broad causes:
- Decreased production of RBCs and/or hemoglobin
- Increased loss or destruction of RBCs, such as a bleeding disorder (1)
RBCs are the most abundant blood cell by far and make up 40-45% of the blood by volume. Even though RBCs live about four months, the body must manufacture an astonishing two million erythrocytes every second to keep up with the equally high rate of RBC destruction. The anatomy of RBCs is highly specialized to provide optimal oxygen transportation abilities.
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Symptoms of anemia
Because depressed RBCs negatively affect the body's ability to fuel its cells with oxygen, many of the symptoms of anemia revolve around difficulty supplying cells with enough oxygen such as low energy levels and shortness of breath.
Symptoms of anemia include:
- Pale or yellowish skin
- Irregular heartbeats
- Shortness of breath
- Dizziness or lightheadedness
- Chest pain
- Cold hands and feet
- Headache (1)
Now that we know what anemia is and what the symptoms are, let's look more in depth at how RBCs carry oxygen and get into more detail about the etiology of anemia, as well as different forms. One of the most important components of RBCs is hemoglobin, which is the iron-containing component of erythrocytes.
Hemoglobin & Iron
Each RBC contains about 280 million hemoglobin molecules and each hemoglobin molecule contains four heme, nonprotein pigments that contain iron ion (Fe2+) which are able to reversibly combine with oxygen molecules, making oxygen transport possible. Hemoglobin also transports about 23% of carbon dioxide, a metabolic waste product, for excretion (2).
Because the iron in hemoglobin binds oxygen for transport by RBCs, a deficiency of iron can lead to iron deficiency anemia, the most common form. We'll talk about iron-deficiency more shortly. Now that we've reviewed relevant erythrocyte anatomy and physiology, let's move on to the different forms of anemia.
Forms of anemia
Primary or secondary anemia can result from many different causes. In this section we'll review some of the most common kinds.
Iron deficiency anemia
We touched on this form of anemia earlier. Iron is critical for the manufacture and proper function of RBCs. Iron deficiency primarily results from inadequate intake or absorption, excessive loss through bleeding, or increased iron demand, and it is the most common form of anemia. Individuals eating a strict vegetarian or vegan diet are among the most likely to have inadequate iron intake (3). Iron malabsorption is common with gastric ulcer, parasites, H. pylori infection (4), hypochlorhydria, and in digestive disorders like Crohn's and celiac disease (5).
Increased iron loss is common in women with heavy menses and in cases of internal bleeding (6). The presence of blood in the stool, especially dried blood that resembles coffee grounds is a strong indication of intestinal bleeding. An occult blood test can also identify blood in the stool that is not visible. When diagnosing iron deficiency anemia, we include more serum markers than with some other forms of anemia, like megaloblastic anemia. An anemia panel for iron deficiency that we use in our clinic includes ferritin, serum iron, UIBC, transferrin saturation, and an CBC w/ differential (at a minimum for comprehensive diagnosis...we sometimes include other markers as well).
Megaloblastic anemia is also known as "B12 deficiency anemia" because it is caused by a lack of vitamin B12 and/or folate. Both of these B vitamins are required for erythropoesis, or RBC synthesis. Pernicious anemia (PA) is a common cause of B12 deficiency and megaloblastic anemia, and results from an inability to produce intrinsic factor, which binds to B12 in the stomach and makes absorption in the small intestine possible. PA can also be autoimmune and is confirmed with a positive intrinsic factor antibody blood test. To learn more about megaloblastic anemia, refer back to our recent post on B12 injections.
As we discussed in that post, another common underlying cause of B12 deficiency is a strict vegetarian or vegan diet that does not include any fish or shellfish. Microalgae like spirulina are often believed to contain B12, but instead mostly contain B12 analogues that not only are inactive in the body, they actually block the absorption of usable B12! We don't recommend spirulina for B12, as it can actually contribute to deficiency by blocking absorption of active B12 (7).
Another interesting aspect of megaloblastic anemia we have observed clinically is a relationship between Small Intestine Bacterial Overgrowth (SIBO) and megaloblastic anemia. It's fairly well known that SIBO can push B12 low by preventing absorption, and it can also increase folate (8). Some of the SIBO bacteria produce folate, and what we have observed clinically is that sometimes after treating SIBO, B12 comes back up and folate levels drop, so it can be worth retesting both of these B vitamins after treating SIBO in cases of anemia, as both can change significantly with successful SIBO treatment.
Anemia of chronic inflammation
This type of anemia is secondary to chronic inflammation and is initiated by the activation of inflammatory cytokines like interleuken-6 (IL-6). Anemia that presents with elevated inflammatory cytokines may indicate anemia secondary to inflammation. The spike in cytokines leads to inflammation by several mechanisms:
- Increases hepatic production and secretion of hepcidin, a peptide which inhibits iron transport and absorption
- Hepicidin also prevents the stores from being released and utilized
- Suppresses erythroid precursor proliferation in the bone marrow
- Inhibits erythropoietin from the kidney
- Shortens lifespan of RBCs (9)
Chronic disease can also produce a similar type of anemia. Chronically increased WBC production to support an elevated immune response can come at the expense of RBC production and lead to decreased erythropoesis.
In hemolytic anemia, RBC plasma membranes rupture prematurely and release hemoglobin into the bloodstream. This can overload and damage the glomeruli units in the kidneys that filter blood. Hemolytic anemia can result from many different causes, including inherited defects like altered RBC enzymes, or from exogenous influences like parasites and toxins (10).
Thalassemia is a related group of hereditary hemolytic anemias, which are characterized by deficient synthesis of hemoglobin. In thalassemia, RBCs are small (microcytic), pale (hypochromic) and short-lived. We'll get into terms for the size and color of RBCs shortly.
Sickle cell disease
Sickle cell anemia is characterized by misshapen RBCs that contain an abnormal kind of hemoglobin and as a result become long, sickle-shaped and unable to carry oxygen. As a result of their abnormal shape, sickle cells rupture easily and die prematurely, resulting in low RBCs. Sickle cells also clump together and can cause blockages in blood vessels (11).
Describing anemic RBCs
Different types of anemia are described in terms of the size and color of the RBCs.
- Large - macrocytic
- Medium - normocytic
- Small - microcytic
- High - hyperchromic (or megaloblastic)
- Medium - normochromic
- Low - hypochromic
We can see how the types of anemia already discussed can fall into these categories:
- Mirocytic hypochromic:
- Iron deficiency
- Anemia of blood loss
- Anemia of chronic inflammation / disease
- Normocytic normochromic:
- Anemia of chronic inflammation / disease
- Anemia of acute blood loss
- Hemolytic anemia
- Sickle cell
- B12/folate deficiency
- Pernicious anemia
These distinctions will come into play into the next section on lab testing. One primary way different types of anemia are distinguished from each other is by looking at color and size of the RBCs.
Lab testing for anemia
There are many anemia patterns, as anemia can have many different etiologies. These manifest differently on labwork. Anemia is primarily diagnosed through the RBC section of the Complete Blood Chemistry (CBC). We'll go over those in this section, discuss some patterns and also a few other markers that can be useful to run.
Anemia in general is identified by depressed RBCs, hemoglobin (HGB) and hematocrit (HCT). From there we look first at Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC) to begin to distinguish different types. Red Blood Cell Distribution Width (RDW) is also useful, especially when mixed anemia is present.
- Anemia is defined as: ideal ranges
- Low RBCs (below the following ideal range) (M) 4.4-4.9 (F) 3.9-4.5
- Low HGB (below the following ideal range) (M) 14-15 g/dL (F) 13.5-14.5 g/dL
- Low HCT (below the following ideal range) (M) 39-55% (F) 37-44%
- MCV looks at cell size: defined as
- Depressed - microcytic <80 fL
- Normal - normocytic 80-100 fL
- Elevated - macrocytic >100 fL
- MCH & MCHC look at cell color: defined as
- Depressed - hypochromic MCH <85 pg MCHC <32 g/dL
- Normal - normochromic MCH 85-92 pg MCHC 32-36 g/dL
- Elevated - hyperchromic MCH >92 pg MCHC >36 g/dL
Let's look at these markers in a little more detail before moving on to other important anemia markers.
- RBCs: the absolute number of cells per liter of blood, which if low may indicate deficient synthesis, increased destruction, or excessive blood loss. High RBCs are associated with high altitude, dehydration, bone marrow disorders or renal disorders.
- Hemoglobin (HGB): The main iron-containing oxygen-transport metalloprotein in RBCs which carries oxygen to the cells and carbon dioxide to the lungs for expiration.
- Hematocrit (HCT): A measurement of the RBC-containing fraction of whole blood.
- Mean Corpuscular Volume (MCV): The average volume of an RBC, which is used to distinguish microcytic, normocytic and macrocytic anemia from each other.
- Mean Corpuscular Hemoglobin (MCH): The average mass of hemoglobin per RBC.
- Mean Corpuscular Hemoglobin Concentration (MCHC): The average concentration of hemoglobin in the cells. This is used to distinguish between hypochromic, normochromic and megaloblastic (hyperchromic) anemia.
- Red Blood Cell Distribution Width (RDW): This is a measure of the variation in RBC size. High RDW may indicate a mixed anemia like concurrent microcytic and macrocytic or early stage anemia when there is more variation in the size of RBCs being produced.
Next, we'll talk about how iron status can impact the presentation of anemia before talking about how to correctly identify and treat the root cause.
Iron markers and disorders
Because of the crucial role iron plays in oxygen transport and anemia, iron disorders overlap with anemia quite a bit. Iron analysis markers are useful in classifying some types of anemia and distinguishing anemia from non-anemia iron disorders. Iron is also essential for erythropoiesis (RBC creation) and DNA synthesis (12). Iron disorders are a large subject all on their own, which we may cover in a future post. We'll just discuss iron here briefly as it relates to anemia.
Iron-deficiency anemia is a form of microcytic hypochromic anemia characterized by depressed ferritin, serum iron and iron saturation and elevated TIBC and transferrin. There can be many causes of iron-deficiency anemia, many of which involve either reduced iron intake or absorption, or increased blood loss, or both.
Common causes of iron-deficiency anemia:
- Reduced iron intake:
- Evaluate diet for iron intake, vegetarian/veganism
- Heme iron vs non-heme iron
- Reduced iron absorption:
- H. pylori
- Celiac disease
- Parasites (hookworms, roundworms, pinworms)
- Increased blood loss:
- Gastric ulcer
- Internal bleeding
- Heavy menses
- Occult blood in stool
One thing we often see in our office is vegetarians and vegans who are deficient in iron, despite making a concerted effort to eat iron-rich vegetable sources like spinach. Vegetable sources of iron contain non-heme iron, which must be converted into heme iron to be utilized in the body. In contrast, animal sources of iron are much higher in heme iron. One of the best sources is red meat. As we discussed in our previous post on B12 injections, plant foods do not contain B12. Consequently, strict vegans and vegetarians who do not eat any fish or shellfish are at increased risk of B12 deficiency, as well as iron deficiency.
Because iron status is such a large subject on its own, we will continue the iron discussion in a future post with information on iron overload, non-anemia iron deficiency and hereditary hemochromatosis. Now that we've covered some of the common markers, let's emphasize focusing on root-cause diagnosis before putting it all together with some anemia patterns.
What's the root cause?
As we have seen in many other cases, it's critical to correctly identify the underlying root cause of anemia. For example, just within the category of iron deficiency anemia, it is important to identify if a person is anemic because of a yet undaignosed H. pylori infection, or the anemia could be secondary to heavy menses that are depleting iron. These are just two of many possible root causes of iron deficiency.
Lab testing to order
The markers we talked about earlier like RBCs, HCT, MCV, MCH, MCHC and RDW are all part of a standard CBC. That is a great starting point. Other important markers to consider are iron status markers like ferritin, serum iron, UIBC, and transferrin saturation if iron deficiency anemia is suspected. We will go into these more in our upcoming post on iron. If, on the other hand megaloblastic anemia is suspected, markers of B12 and folate status are important (such as serum B12, serum folate, RBC folate, homocysteine, Methylmalonic Acid (MMA), and possibly holotranscobalamin if available in your area. Pernicious anemia can be confirmed with a positive intrinsic factor antibody in cases of suspected pernicious anemia.
Start with the RBC breakdown on the CBC to determine whether the anemia is micro-, normo- or macrocytic and hypo-, normo- or hyperchromic. Once you've identified the type, look at possible underlying causes and order further testing as appropriate, whether it's a SIBO breath test, an iron panel, inflammatory cytokines or MMA and folate. Getting a serum B12, homocysteine, and ferritin value are also standard orders for nearly every patient in our clinic (on top of a CBC with differential).
If you are vegan or strictly vegetarian, you may need to supplement with vitamin B12, iron, zinc, and possibly other trace minerals (best to check and confirm deficiencies as excessive amounts of some nutrients like iron or zinc can be toxic. B12 is generally considered to be safe with low chances for toxicity even with excessive doses). Some people decide to become vegetarian or vegan for health reasons. While there are conditions that can improve from various diets, vegetarian and vegan diets included, there are times when the health benefits can be exaggerated or the negative health impacts can be ignored. An example is the "What the Health" documentary. This movie has been the subject of several of our patients who have inquired about whether they should be eliminating animal products from their diet.
Unfortunately, this movie does a great job of touching into peoples emotions, but is very poor in citing any well-done, peer-reviewed research (although some people watching it think that it must be valid evidence). It is our professional opinion that the research cited in this movie is of poor quality and that the perspective was biased without considering both sides of the issue. We do not generally recommend vegetarian or vegan diets for health reasons in most cases. However, we completely understand ethical / religious reasons for choosing these kinds of diets and support clients who consciously choose these kinds of diets with recommendations for how to avoid nutrient deficiencies (especially by supplementing with some of the nutrients listed above and choosing certain foods that are rich in nutrients that are commonly deficient). For pescatarians (or vegetarians that are comfortable eating things that do not have faces), clams are a fantastic source of vitamin B12 and iron (plus other minerals). Oysters are the highest source of zinc. Just one or two servings of clams per week can correct some of the nutrient deficiencies that are common in vegetarians / vegans who are willing to eat shellfish.
If you struggle with some or all of:
- Pale skin
Plus you have some of the risk factors like:
- Vegan diet
- Excessive bleeding
- Gastrointestinal (gut) infections
- Extreme exercise
It is worth getting lab testing from a functional medicine doctor who can assess for functional ranges and help identify the root cause(s) behind anemia or other conditions that can also cause some of the same kinds of symptoms.
Check back soon for our future posts which will expand this information. We'll get more detailed about iron markers and other anemia patterns.
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- Moschonis G, Papandreou D, Mavrogianni C, et al. Association of Iron Depletion with Menstruation and Dietary Intake Indices in Pubertal Girls: The Healthy Growth Study. BioMed Research International. 2013;2013:423263. doi:10.1155/2013/423263.
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- Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. Journal of Clinical Investigation. 2004;113(9):1271-1276. doi:10.1172/JCI200420945.
- Dhaliwal G, Cornett PA, Tierney LM. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599-606.
- Dubert M, Elion J, Tolo A, et al. Degree of anemia, indirect markers of hemolysis, and vascular complications of sickle cell disease in Africa. Blood. 2017;130(20):2215-2223.
- Wu CJ, Krishnamurti L, Kutok JL, et al. Evidence for ineffective erythropoiesis in severe sickle cell disease. Blood. 2005;106(10):3639-3645. doi:10.1182/blood-2005-04-1376.