In practice, anemia often appears in the blood count, accompanying many acute and chronic diseases. Clarification is definitely recommended because already a lowered haemoglobin value alone can be the first important hint for an undetected underlying disease. Often, alimentary anemia like the iron deficiency anemia, the vitamin B12-deficiency-anemia or the folic acid anemia, are at the center of diagnostics. This is why, in the following article, you will learn more about these diseases.
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Iron deficiency anemia

Image: “Blood smear of a patient with Iron deficiency anemia at 40x enhancement” by Roberto J. Galindo. License: CC BY-SA 3.0

Iron Deficiency Anemia

Definition of Iron Deficiency Anemia

Iron deficiency is the most common cause for anemia worldwide. An iron deficiency anemia, like the name of the disease already tells, is anemia caused by substantially decreased iron reservoirs.

You can read more on hemolytic anemia here.

Aetiology and Epidemiology of the Iron Deficiency Anemia

The production of erythrocytes and haemoglobin is largely dependent on the availability of erythropoietin (epo) and iron.

The most frequent reasons for critically lowered iron values are chronic bleeding – either through increased menstrual bleeding (hypermenorrhea) or a pathological bleeding caused by a gastric ulcer, pregnancy without sufficient substitution of iron or a parasitic infestation (parasitic disease).

Rarer possible causes for an iron deficiency anemia are disruption of the resorption or malnutrition.

With a dissemination of 35%, the iron deficiency anemia represents the most common cause for anemia. Roughly 5-10% of menstruating women suffer from iron deficiency anemia. Men are much more rarely affected by anemia.

Symptoms of Iron Deficiency Anemia

An iron deficiency anemia has the same symptoms than any other anemia:

Angular cheilitis as marked by the oval

Image: “Angular cheilitis as marked by the oval” by James Heilman, MD. License: CC BY-SA 3.0

  • tachycardia
  • fatigue
  • weakness
  • lack of concentration
  • diminished strength

Further clinical symptoms are dry skin, possible headache and hair loss.

Nail dystrophy, glossitis (Hunter-Glossitis) and atrophies in the area of the mouth (angular cheilitis), throat and the oesophagus, are typical symptoms for the Plummer-Vinson syndrome. A particular symptom is pronounced sensitivity to cold.

Diagnostics and Differential Diagnosis of Iron Deficiency Anemia

A complete blood count is important for adequately diagnosing iron deficiency anemia. Normally, a hypochromasia is displayed in the laboratory diagnostics in combination with a microcytosis and a reduced value of serum ferritin (< 15µg/l). The haematocrit is lowered.

Depending on the severity of the anemia, the number of erythrocytes can also be reduced. For further clarification, it is necessary to measure the reactive increased value of transferrin, as well as the concentration of haemoglobin of the reticulocytes (lowered, < 28pg).

Iron deficiency anemia

Image: “Blood smear of a patient with Iron deficiency anemia at 40x enhancement” by Roberto J. Galindo. License: CC BY-SA 3.0

The diagnostics of the iron deficiency anemia is not always easy. For instance, a folate deficiency occurring simultaneously can compensate the microcytosis and, therefore, falsify an important laboratory parameter for the iron deficiency anemia.

It is important to consider that because of counterproductive diagnostics, a possible disease may not be diagnosed, leading to the anemia and the actual cause being overlooked. Officially, not applying the required therapy only counts as malpractice, but for the patient, this can have serious consequences in reality.

In case the result is uncertain, it is important to take a thalassemia into consideration.

Therapy of Iron Deficiency Anemia

In case the finding of an iron deficiency anemia is definite and the diagnostics for a different underlying disease (like, for instance, a duodenal ulcer or a colon carcinoma) turn out to be negative, the primary therapeutic target is a correcting the negative iron balance through the substitution of iron.

The following rules should be kept in mind:

  1. If possible, iron should be applied orally. Only in case of a strong incompatibility and special indication, the iron should be substituted parenteral.
  2. The recommended daily dose is between 50 and 150 mg. Resorption is highest on an empty stomach. In case this is not tolerated by the patient, the iron should be taken during meals.
  3. A rule of thumb for the application duration of the substitution of iron is that, after a normalisation of the value of haemoglobin, monitor the progress!  The substitution of iron should be resumed for the same period of time it took for the haemoglobin value to normalize. Normally, the patient should substitute iron for several months. In case the duration of the substitution is too short, it leads, in all likelihood, to empty iron reservoirs, ultimately leading to an anemia.
  4. In case the value of haemoglobin does not increase during the regular follow-up, both the therapy and the diagnosis should be checked. Other causes which have not been taken in account so far should be researched.

Side Effects of the Therapy of Iron Deficiency Anemia

The most common side effects are stomach problems with nausea and obstipation, but also diarrhea. Often, the stool turns darker or black, which is harmless as long as there are no other symptoms.

Course and Follow-up of Iron Deficiency Anemia

Only a few days after the initial substitution of iron, the increasing erythropoiesis becomes obvious in the blood smear through a reticulocytosis. As a result of the substitution, the expected increase of the haemoglobin is roughly around 0.1 g/dl per day. In case this is not confirmed by the follow-up, there is either a continued loss of iron, or the substitution of iron itself is defective or incorrect.

To exclude the latter, the compliance of the patient should be checked. If checked and there are no hints for defective compliance, the diagnosis or the choice of therapy (enteral/parenteral) should be questioned.

Note: The causes for an iron deficiency anemia are hypermenorrhea, pathological, mostly intestinal bleedings, and disorder of absorption as well as malnutrition. Important symptoms are B-symptoms like fatigue and weakness, as well as the typical symptoms of the Plummer-Vinson’s-syndrome. A specific sign is the sensitivity to cold. In case of an iron deficiency anemia, the treatment of the cause has the highest priority. The therapy of the iron deficiency anemia is a combination of treating the underlying disease, as well as a substitution of iron.

Megaloblastic Anemia

Microscopy image of a megaloblastic anemiaIn case the forming of DNA in new cells is prevented, which can be caused by different reasons, impacts on the growth of the progenitor cells of the erythrocytes are possible.

The so-called erythroblasts show typical morphological changes, which are called megaloblastic.

Every megaloblastic anemia produces macrocytic erythrocytes, but not every macrocytosis comes with a megaloblastic anemia. The most common causes for a megaloblastic anemia are:

  • vitamin B 12-deficiency (frequent)
  • folate deficiency (frequent)
  • malignant diseases (moderately frequent)

In the following section, the two first-mentioned causal diseases are presented in more detail.

Vitamin B 12-Deficiency Anemia

Definition of vitamin B 12-Deficiency Anemia

structural formula vitamin b 12The vitamin B 12-deficiency-anemia is a macrocytic-hyperchromatic, megaloblastic anemia with a lower level of vitamin B 12.

The most common cause is a disruption in the resorption of the vitamin. In case the disrupted resorption is caused by a type-A-gastritis with a resulting intrinsic factor-deficiency, the disease is called pernicious anemia.

A disrupted resorption in the area of the ileum after resection, Crohn’s disease or exocrine pancreatic insufficiency can cause a megaloblastic vitamin B 12-deficiency-anemia, but they aren’t classified as pernicious anemia.

The evidence of autoimmunity alone justifies the finding of a pernicious anemia.

Etiology of Vitamin B 12-Deficiency Anemia

The daily intake of vitamin B 12, which is also known as Cobalamin, is only around 2-3µg. However, a disruption of the incorporation, resorption, synthesis or storage of the vitamin can lead to serious symptoms. This mainly occurs in areas of the body where the vitamin is essential, especially in the bone marrow.

In case there is an insufficient amount of vitamin, this can have negative effects on the erythropoiesis. As a coenzyme of the metabolism of nucleic acids and lipids, it plays an important role in the production of active folate acid. If production is disrupted due to Cobalamin deficiency, the correct forming of the DNA is no longer possible which leads to an anemia in the form characterized above.

Causes of Vitamin B 12-Deficiency-Anemia

Alimentary Causes (Vegetarianism):
As the human being has to take in vitamin B 12 orally and said vitamin is mainly found in animal products like meat, fish, milk, and eggs, a vegetarian lifestyle can lead to a vitamin B 12 deficiency-anemia. However, not every vegetarian necessarily has to develop an anemia.

No other vitamin can be stored better in the liver over longer periods than vitamin B 12, so that a supply can last for months or even years. Alimentary states of deficiency are very rarely the causes for a vitamin B 12 deficiency-anemia.

Anacidity Caused by Atrophic Gastritis:
One of the more common causes of a vitamin B12-deficiency-anemia is the anacidity in the milieu of the stomach. In case the milieu of the stomach is not balanced and the release and binding of the vitamin to the proteins of transportation is disrupted, a disruption of the resorption can occur, which, if chronically, can lead to an anemia.

Intrinsic-Factor (Type-A-Gastritis):
The transport mechanism can also be disrupted in other places. T-cells can destroy parietal cells (parietal cells of the stomach), triggered by an autoimmune reaction.

The parietal cells produce the intrinsic factor, which is necessary for the transportation of vitamin B 12. As the intrinsic factor is destroyed alongside with the destruction of the parietal cells and the forming of antibodies, the binding of vitamin B 12 to glycoprotein does either not take place at all or only to a lesser extent. Transportation and resorption of the vitamin are severely disrupted.

Further Causes for a Disrupted Absorption:
The cause for a disrupted absorption can also be directly located in the terminal ileum, where the vitamin is re-absorbed through the intestine. Every impairment of the intestine in that area can lead to absorption problems. The main causes are:

  • Crohn’s disease
  • Resection
  • Bad bacterial settlement of the intestine
  • Diphyllobothrium

Clinic of Vitamin B 12-Deficiency-Anemia

Besides the typical symptoms of anemia like lethargy, pale skin and pale mucosa, a patient with vitamin B 12-deficiency-anemia may also exhibit a sub-jaundice (higher level of bilirubin in the serum), which is the result of the disrupted turnover of the erythrocytes in the bone marrow.


Image: “Foto de un campo 10x de un frote sanguíneo mostrando una neutropenia importante” by Roberto J. Galindo. License: CC BY-SA 3.0

Neutropenia and Thrombocytopenia:
Since all cells are affected by the disruption, neutropenia and thrombocytopenia can occur at an advanced stage, resulting in thrombocytopenic purpura (haemorrhagic diathesis) and an overall weakening of the immune system.

Subacute Combined Degeneration of the Spinal Cord:
In comparison to other anemia, the vitamin B 12-deficiency-anemia can also cause neurological disorders, which can vary from an isolated peripheral neuropathy to a subacute combined degeneration of the spinal cord.

Clinical symptoms are the disruption of memory, loss of concentration and sensitivity, paraesthesia and reduced reflexes; even muscular paralysis is possible. The reason for the occurrence of these diseases is a prolonged vitamin B 12-deficiency which leads to a de-marrowing of the myelin sheath, especially in the area of the dorsal and lateral column system of the spinal cord (demyelinisation).

Further clinical signs, which do not exclude other types of anemia, are the following:

  • loss of appetite
  • abdominal discomfort
  • diarrhea
  • obstipation
  • glossodynia and atrophic tongue (Hunter-glossitis)

Diagnosis and Differential Diagnostics of Vitamin B 12-Deficiency-Anemia

Measurement of the Serum Level of Vitamin B 12:
In most cases (90%), a lower level of vitamin B 12 in the serum is proof enough. However, this value is not 100% reliable because it can be falsified by proliferative diseases of the bone marrow or by diseases of the liver. In addition, there are also patients who already exhibit symptoms of anemia in the lower normal range.

In these cases, determining the serum concentration in the methyl malonic acid and the homocysteine acid should be considered, because both values increase in case of a vitamin B 12-deficiency-anemia.

Blood Count:
As in most cases, a blood count is a first hint for a possible anemia and normally precedes the measurement of the vitamin B 12 level, a lower value of haemoglobin alone, in combination with macrocytosis and hyperchromia, should hint towards a diagnosis of a vitamin B 12-deficiency-anemia.

In comparison to an iron deficiency anemia, all of the cells are affected by a vitamin B 12-deficiency-anemia and therefore lower values of leucocytes, as well as thrombocytes, can be found (pancytopenia).

If there is proof of vitamin B 12 deficiency, the cause has to be found. To distinguish between a disruption of absorption and an intrinsic-factor-deficiency, the Schilling-test, with radioactively marked vitamin B 12, can be conducted.

Evidence of Antibodies:
In case of a suspected pernicious anemia, a proof of antibodies for the intrinsic-factor, as well as for the parietal cells of the stomach, should be conducted.

The most common cause for a vitamin B 12-deficiency-anemia can be found in the stomach; that is why a gastroscopy is indicated for every patient with a vitamin B 12-deficiency. With this procedure, a stomach carcinoma, as well as an atrophic gastritis, can either be excluded or proven.

Therapy of Vitamin B 12-Deficiency-Anemia

The therapy depends on the underlying disease. Additionally, vitamin B 12 is substituted. Normally, a high dose of hydroxic cobalamin (1000µg) is given parenteral once a week. After the values have reached a normal level, a lifelong therapy with 1000µg, every six months, is indicated.

Course and Prognosis of Vitamin B 12-Deficiency-Anemia

If the underlying disease is identified and treated and the substitution of vitamin B 12 is administered in the right way, the anemia declines within a couple of days.

The neurological symptoms, caused by a vitamin B 12-deficiency-anemia, can, when untreated, lead to lasting neurological damage. Because of the atrophic and aplastic changes of the mucosa, the risk for a stomach carcinoma, or other carcinoid diseases, is higher for patients with a pernicious anemia.

Note: The most common cause for a vitamin B 12-deficiency-anemia is a type-A-gastritis. Besides the typical symptoms of anemia, the patients also show signs of neurological disruptions. Diagnostically, the blood count, the measurement of the level of vitamin B 12, as well as the determination of the antibodies, is path-breaking. Alongside treating the underlying disease, a substitution with vitamin B 12 is necessary.


Definition of Folate-Deficiency-Anemiastructural formula folic acid

Like vitamin B 12-deficiency-anemia, the folate-deficiency-anemia is a megaloblastic anemia. The most common cause is nutrition with an insufficient folate acid level.

Etiology of Folate-Deficiency-Anemia

From a biochemical point of view, the folate acid is a term for a whole group of so-called derivate of pteridine. These are produced by plants, as well as microorganisms. Vegetables, salads, fruits, milk, wholegrain products and offal are a good source of folate acid. That is why before the pharmacological substitution, the substitution with cattle liver was the first choice.

As the recommended daily intake is around 400 µg and, in case of bad nutrition with too less folate acid, the body’s reserves of 5 mg folate acid are consumed quite quickly, symptoms of folate-deficiency can occur within a couple of weeks.

Beside a nutrition low in folate acid, other possible causes are:

  • disease of the liver
  • alcohol abuse
  • a large resection of the small intestine
  • pregnancy
  • anticonvulsive drug
  • a chronic haemolysis
  • a gluten-sensitive enteropathy
  • a tropical sprue
  • overcooked food

Clinic of Folate-Deficiency-Anemia

A folate deficiency leads to the typical symptoms of anemia. Atrophy of the mucosa in the area of the larynx (dysphagia) or the gastrointestinal tract (meteorism, diarrhea) are signs for a vitamin B 12-deficiency-anemia, as well as a folate deficiency. However, the folate acid does not play a role in the metabolism of the lipids and, therefore, does not cause neuropathies.

Diagnostics of Folate-Deficiency-Anemia

Because the blood count and the findings of the bone marrow also correspond to vitamin B 12-deficiency (macrocytosis, hyperchromia), further testing and determination of other values are important to distinguish between the two megaloblastic anemia.

Therefore, it is important to measure the level of vitamin B 12 to exclude an additional vitamin B 12-deficiency-anemia. Furthermore, the level of folate acid can be determined. This, however, only has little meaning as it can be influenced very easily. Just one meal with folate acid can bring the level of folate acid back to normal. A more reliable parameter is the concentration of folate acid in the erythrocytes.

Therapy of Folate-Deficiency-Anemia

Normally, treatment of the actual disease (alcohol abuse, anorexia nervosa, etc.) is enough. However, depending on the severity of the disease, this is not always easy and, therefore, difficult to implement. In such cases, it is important that the dose for substitution is high. To eliminate the causes and for prophylactic reasons, a daily intake of 5 mg of folate acid is recommended to be applied orally.

Complications of Folate-Deficiency-Anemia

In case a folate deficiency stays untreated over a longer period of time, accelerated development of arteriosclerosis can be a consequence. The result of arteriosclerosis can be, at the worst, myocardial or brain infarction.

In case of folate acid insufficiency during pregnancy, neural tube defects can be the result for the child during the embryonic phase. Also, osteoporosis is suspected to worsen when accompanied by a folate deficiency.

Note: Without checking the neurological state through anamnesis and clinical examination, folate-deficiency-anemia can be confused with a vitamin B 12-deficiency-anemia because of the similarity in the blood count and the clinic. That is why it is important to know that a folate deficiency alone does not lead to neurological symptoms.

Further Alimentary Anemia

Further alimentary anemia are the protein anemia and the scurvy anemia.

Review Questions

The answers can be found below the references.

1. Which statements about the vitamin B 12 (Cobalamin) are correct?

  1. Its main structure is similar to the structure of porphyrins.
  2. It has a co-ordinative binding of Fe².
  3. Its absorption takes place in the stomach.
  4. It catalyses intramolecular rearrangement of alkyl radical.
  5. A lower absorptions leads to an iron deficiency anemia.
  1. Only 1 and 3 are correct.
  2. Only 1 and 4 are correct.
  3. Only 2, 3 and 5 are correct.
  4. Only 3, 4 and 5 are correct.
  5. Only 1, 3, 4 and 5 are correct.

2. What is dependent on vitamin B 12?

  1. The re-arrangement of methylmalonyl-coa to succinyl-coa
  2. The forming of creatinine of creatininphosphate
  3. The demethylation of methionine to homocysteine
  4. The methylation of noradrenaline to adrenaline
  5. The methylation of phosphatidylethanolamine to phosphatidylcholine

3. The following values are measured in the blood count of an adult: Concentration of haemoglobin 100 g/l, concentration of erythrocytes 2,4 x 1012 and concentration of leucocytes 6 x 109. From which disease does he suffer?

  1. Anemia with a normal amount of haemoglobin per erythrocyte
  2. Anemia with a lower amount of haemoglobin per erythrocyte
  3. Anemia with a higher amount of haemoglobin per erythrocyte
  4. Leucocytosis
  5. Leukopenia


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