ANEMIA IN HYPOTHYROIDISM

A. Introduction
Hypothyroidism, also known as underactive thyroid, is a condition where the thyroid gland is unable to secrete several types of hormones, including T3 and T4 hormones. The main causes of hypothyroidism include autoimmune diseases such as Hashimoto’s thyroiditis, surgical removal of the thyroid, and radiation therapy.1 In the early stages of this disease, symptoms may not appear, but in later stages it can cause symptoms such as obesity, joint pain, infertility, and heart disease. .2 In addition to these conditions, many studies have shown that hypothyroidism can cause anemia.3
B. Hypothyroidism
1. Classification
Based on the cause, hypothyroidism can be divided into primary and secondary hypothyroidism. Primary hypothyroidism is hypothyroidism that occurs due to damage to the thyroid gland and further classification can be seen in table 1. In this condition, the thyroid gland is usually enlarged as a compensatory process. Meanwhile, secondary hypothyroidism is a failure of stimulation of the pituitary system to a healthy thyroid gland. Most cases of hypothyroidism are primary hypothyroidism.

 

Klasifikasi Hipotiroidisme Primer berdasarkan Penyebab.4

Classification of Primary Hypothyroidism by Cause.44

kongenital

kongenital

2. Epidemiology
The incidence of hypothyroidism varies depending on the population of a country. In the United States, 0.3% of the population has overt hypothyroidism, defined as elevated serum TSH and decreased free T4 hormone (fT4) concentrations, and 4.3% have mild or subclinical hypothyroidism. Subclinical hypothyroidism is defined as an increase in serum TSH concentration without a corresponding decrease in or fT4. The incidence of hypothyroidism is higher in older women in some racial and ethnic groups. Subclinical hypothyroidism can progress to overt hypothyroidism. Neonatal screening programs for congenital hypothyroidism show that hypothyroidism occurs in 1 in 3000 newborns.
C. Anemia
Anemia is a condition in which the body does not have enough healthy red blood cells to adequately transport oxygen to all body tissues. This includes the size, number, and function of erythrocytes.5 Anemia is a disease that is often experienced by humans in the world. In America, 3,000,000 people have anemia.
1. Classification
Anemia can be classified based on how it looks under the microscope. This appearance can also narrow the examination of the etiology of the anemia. The appearance of anemia under the microscope can include size and color. Erythrocyte size is divided into microcytic (small), normocytic (normal), and macrocytic (large). Meanwhile, the color is divided into hypochromic and normochromic. Classification and identification of causes can be seen in Figure 1. The color of erythrocytes often follows their size, namely microcytic accompanied by hypochromic and normocytic accompanied by normochromic. Therefore, the classification of anemia only considers the size and number of reticulocytes. The reticulocyte count reflects the activity of the spinal cord that produces red blood cells. Higher reticulocyte levels indicate increased bone marrow activity which is a sign of a pathological process.

Classification of anemia based on size (MCV) and reticulocyte count.6

Classification of anemia based on size (MCV) and reticulocyte count.6

Microcytic anemia, characterized by a mean corpuscular volume (MCV) <80fL, is a hallmark of several iron deficiency diseases. In addition, diseases that can also cause microcytic anemia are sideroblastic anemia, anemia due to chronic inflammation, and thalassemia. Meanwhile, macrocytic anemia occurs mainly in folic acid and vitamin B12 deficiency. This happens because folic acid and vitamin B12 play a role in the formation of nucleic acids at the beginning of erythrocyte production. Deficiency of folic acid and vitamin B12 causes an extension of the time of nucleic acid production followed by cell growth so that the cells formed are large. The third type of anemia is normocytic anemia. Under the microscope, the size of the erythrocyte can be assessed by comparing it to the nucleus of a large lymphocyte. Normally, an erythrocyte is approximately the same size as a large lymphocyte nucleus (see Figure 2).

The appearance of erythrocytes under a microscope. a. Normocytic erythrocytes, b. microcytic erythrocytes in iron deficiency, c. macrocytic erythrocytes in vitamin B12.7 deficiency

The appearance of erythrocytes under a microscope. a. Normocytic erythrocytes, b. microcytic erythrocytes in iron deficiency, c. macrocytic erythrocytes in vitamin B12.7 deficiency

2. Normal Erythropoiesis
The initial formation of blood cells occurs in the bone marrow from one type of cell, a pluripotent hematopoietic stem cell, which then differentiates into a variety of blood cells. Furthermore, the cells will continue to undergo differentiation to be more specific. The initial cells that are specific as erythrocytes are proerythroblasts. The differentiation of one type of hematopoietic stem cell into various types of cells is influenced by various chemical mediators present in the bone marrow.
The production of red blood cells in the circulatory system is tightly regulated so that (1) the number of red blood cells is adequate to provide adequate oxygen transport from the lungs to the tissues, (2) the number of cells is not too large which can obstruct blood flow. This control mechanism can be seen in Figure 3.8

Mechanism of control of red blood cell production.8

Mechanism of control of red blood cell production.8

The level of tissue oxygenation is the main thing that affects the control of red blood cell production. Therefore, in conditions that are very anemic due to bleeding or other conditions, the bone marrow produces large amounts of red blood cells. In addition, destruction due to radiation therapy will cause bone marrow hyperplasia as a compensatory mechanism for anemia. Highland areas will also stimulate the production of red blood cells due to low oxygen levels in the air. Various diseases that can inhibit tissue oxygenation by the circulatory system such as heart failure and lung disease can also stimulate the production of red blood cells.

3. The Role of Thyroid Hormones in Erythropoiesis

3. The Role of Thyroid Hormones in Erythropoiesis

3. The Role of Thyroid Hormones in Erythropoiesis

The shared function of thyroid hormones is mediated by the attachment of triiodothyronine (T3) and thyroxine (T4) to specific nuclear receptors. Preliminary studies of the effect of thyroid hormone on the process of hematopoiesis (including erythropoiesis) in umbilical cord blood, peripheral blood, and bone marrow rich in CD34+ hematopoietic stem cells suggest that T3/T4 hormones have a role in their growth and apoptosis processes. Previous investigations have also shown that T3/T4 hormone levels affect clonogenicity and apoptosis induction in umbilical cord blood, peripheral blood, and bone marrow. Other studies also prove that there is thyroid hormone in peripheral blood, umbilical cord blood, and human bone marrow
In vitro studies have been conducted to determine the direct effect of thyroid hormone on thyroid receptor (TR) expression. The results showed that TRα-1 expression was lower in normal CD34+ cells with higher T3/T4 levels than controls. This indicates that high levels of T3/T4 hormones inhibit TR expression. Meanwhile, at lower thyroid hormone levels than the control, there was a reduction in mRNA expression due to a lack of thyroid hormone. Therefore, thyroid hormone levels that are too high or too low can decrease the activity of CD34+ hematopoietic stem cells. Further research is needed on apoptotic and anti-apoptotic activity in hematopoietic stem cells, in terms of thyroid hormone disorders (in this case hypothyroidism and hyperthyroidism). This study was carried out by assessing the expression of several genes in hematopoietic stem cells with various levels of thyroid hormone. The graph of the results of the gamar test can be seen in Figure 5. Gene expression was assessed using qRT-PCR.9

Expression of several genes in CD34+ hematopoietic stem cells with various levels of thyroid hormone.9

Expression of several genes in CD34+ hematopoietic stem cells with various levels of thyroid hormone.9

D. Anemia in Hypothyroidism
Anemia often occurs in thyroid disease, both hyperthyroidism and hypothyroidism. It was recorded that 14.6% of patients with overt hyperthyroidism had anemia, but only 7.7% of patients with hypothyroidism had anemia. Several mechanisms have been discovered by researchers regarding how thyroid hormone disease affects anemia.10
As mentioned above, thyroid hormone has a direct effect on the proliferation of erythrocyte precursor cells. In addition, thyroid hormone also increases erythropoiesis by stimulating gene expression and erythropoietin production by the kidneys. However, the mechanism by which hypothyroidism can cause anemia is a complex mechanism that can include decreased bone marrow stimulation, decreased erythropoietin levels, and nutrient deficiencies (vitamin B12, iron, and folic acid).
Research on the effect of thyroid hormone on vitamin B12 has been carried out, patients with autoimmune thyroid disease have a high potential for vitamin B12 deficiency, iron or folic acid deficiency.
In a study by Ying Zhang, thyroid hormone regulates hematopoiesis through the TR-KLF9 (Thyroid Receptor-Kruppel-like factor 9) axis in the formation and maturation of erythrocytes and lymphocytes. Mutations in DUOX2 (Dual Oxide 2) result in a decrease in thyroid hormone production, so that thyroid hormone does not bind much to TR-KLF9 for erythrocyte maturation. This causes anemia in hypothyroidism
In a study by Mancini, thyroid hormone can cause oxidative stress and inflammation that will become chronic. This can cause anemia due to chronic inflammation caused

Thyroid hormone regulation in erythropoiesis via the axis

Thyroid hormone regulation in erythropoiesis via the axis

Conclusion

Various body conditions can affect the production of red blood cells. One of the diseases that can affect the production of red blood cells is thyroid hormone. Thyroid hormone has an effect on erythropoiesis (in this case proliferation and maturation) and has stem cell regulation of hematopoiesis. Hypothyroidism causes a decrease in appetite, so the intake of nutrients and minerals is reduced which can cause anemia. Therefore, clinicians need to consider the possibility of anemia in children with hypothyroidism in determining therapy.

BIBLIOGRAPHY

  1. Hypothyroidism [Internet]. American Thyroid Association. [cited 2019 Aug 10]. Available from: https://www.thyroid.org/hypothyroidism/
  2. Hypothyroidism – Symptoms and causes [Internet]. Mayo Clinic. [cited 2019 Aug 10]. Available from: https://www.mayoclinic.org/diseases-conditions/hypothyroidism/symptoms-causes/syc-20350284
  3. Study Looks at Link Between Anemia and Hypothyroidism [Internet]. EndocrineWeb. [cited 2019 Aug 10]. Available from: https://www.endocrineweb.com/professional/research-updates/thyroid-disorders/study-looks-link-between-anemia-hypothyroidism
  4. Williams R. Williams textbook of endocrinology. 13th edition. Melmed S, Polonsky KS, Larsen PR, Kronenberg H, editors. Philadelphia, PA: Elsevier; 2016. 1916 p. 420-4.
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  6. Ralf DM. All Types of Anemia with Full Anemia Definition Chart and Diagnosis [Internet]. Blood Test Results Explained. 2017 [cited 2019 Aug 10]. Available from: http://bloodtestsresults.com/types-of-anemia-anemia-definition-chart/
  7. Greer JP, editor. Wintrobe’s clinical hematology. Thirteenth edition. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins Health; 2014. 2 p. 593-6.
  8. Hall JE. Guyton and Hall textbook of medical physiology. 13th edition. Philadelphia, PA: Elsevier; 2016. 1145 p. 446-9.
  9. Kawa MP, Grymuła K, Paczkowska E, Baśkiewicz-Masiuk M, Dąbkowska E, Koziołek M, et al. Clinical relevance of thyroid dysfunction in human haematopoiesis: biochemical and molecular studies. European Journal of Endocrinology. 2010 Feb;162(2):295–305.
  10. Szczepanek-Parulska E, Hernik A, Ruchała M. Anemia in thyroid diseases. Polish Archives of Internal Medicine [Internet]. 2017 Mar 28 [cited 2019 Aug 11]; Available from: http://pamw.pl/en/node/3985
  11. Zhang Y., et al. Thyroid Hormone Regulates Hematopoiesis via the TR-KLF9 Axis. American Society of Hematology: Bloodjournal. 2017.
  12. Mancini A, et al. Thyroid Hormones, Oxydative Stress and Inflammation. Hindawi Publishing Coorporation. 2015.

 

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