How Selenium Helps Against Sickle Cell Disease

             As one of many types of anemia, sickle cell disease (SCD) is caused by a genetic condition that results in the malformation of normally round, red blood cells into a banana or sickle-like shape. SCD can vary in symptoms, and in the frequency and severity of painful episodes called crises. Approximately 100,000 Americans have this form of anemia including about 4,000 in Virginia. (1) Over 7.7 million others worldwide have SCD (2), mostly in tropical Africa where this gene mutation originated as a protection against malaria that is frequently fatal in early childhood. Currently, an average of 75 infants are born with SCD in Virginia annually. The highest number of SCD births in the state are in Prince William and Fairfax counties, and Norfolk. The average life expectancy of a person in the U.S. with SCD is 49.3 years for men and 55 years for women. (3) To understand SCD, one must understand anemia in general, as well as how red blood cells are formed and destroyed.

Red Blood Cells – RBCs 

            Red blood cells (RBCs) lack a nucleus and normal cellular organelles like mitochondria. They are far smaller than other human cells and are essentially sacks filled with millions of hemoglobin molecules that hold the oxygen. Due to their small size and ubiquitous function, RBCs constitute 70% of all human cells in the body not including benign intestinal bacterial flora. 2.4 million red blood cells form every second and are far more plentiful than white blood cells or platelets in the blood. (4) Normal RBCs are round and concave in the middle on both sides. They distribute oxygen from the lungs to all other tissues. As they circulate around the body about once per minute, RBCs return to the lungs to release the carbon dioxide waste product mitochondria produce when they burn oxygen to provide energy for cells. (4) When anemia develops, RBC production moves from the bone marrow to the spleen and the rate of RBC generation increases one thousand percent.

RBCs begin developing with a nucleus. However, prior to maturing, macrophage white blood cells extract their nucleus to allow more room for hemoglobin, the four-part molecular configuration that holds the oxygen within RBCs. Like soft rubber, RBCs are extremely flexible so they can squeeze through capillaries that are one third narrower than RBCs are themselves. (4) This tight squeeze facilitates the ability of RBCs to release their oxygen and pick up the waste product of burned oxygen, carbon-dioxide - CO2. With their distorted banana-like shape and a defect that exposes their sticky adhesion molecules to the surface of blood vessels, sickled RBCs often cause clot-like blockages that choke off blood flow, reducing tissue oxygenation. That is what causes severe, painful episodes and gradually, over time, increases organ damage. (4)

The body produces 144 million new RBCs every minute. In fetuses, RBCs develop in the fetal liver. In adults, RBCs are formed in a specialized microenvironment inside the bone marrow of large bones. (4)

Selenium and RBCs

            Biologists consider the chemical element selenium to be the universally protective element. Every human, animal, and almost all plant cells contain selenium. Proteins containing selenium called selenoproteins form the active site of most antioxidants. Thus selenium is essential to both the health and structure of all animal cells. Selenium-based antioxidants clean and detoxify cells, protecting them from damage by oxygen free radicals and toxins like alcohol, heavy metals, and radiation. Selenium is also essential for the functional stability of mitochondria that produce energy for cells by burning oxygen and emitting carbon dioxide. Selenium is critical for both maintaining the prooxidant/antioxidant balance required for cellular homeostasis and maintaining the structural integrity of cells. Like nails connecting wood, selenium molecules connect the lipoproteins that compose the outer cellular membrane.

            Although every human cell contains selenium, it is more concentrated in the cells and organs of the immune system including white blood cell lymphocytes, the liver, kidneys, spleen, thymus, and lymph nodes. The thyroid gland, bone marrow and brain also have higher levels. Because of its antioxidant qualities, selenium also concentrates in red blood cells protecting them from the damaging qualities of the oxygen and CO2 they transport.

            Like water, life itself is impossible without adequate selenium. Because selenium has proven to be the strongest medicinal agent to increase CD4 cell count and thus the strength of the immune system, one could consider selenium to be the fuel that propels immune function. One expert explained that if a person has enough selenium, their immune system will be strong. If selenium is deficient, immunity will be weak.

            Most viruses also require selenium for protection. It helps form their protective outer envelope. Viruses infect and make cells sick by attacking their selenium supply that is primarily located in the antioxidants that keep cells healthy. Viruses replicate at different rates and various viruses require different numbers of selenium atoms to construct their envelopes. Thus, some viruses cause more damage to cells and deplete selenium reserves faster. That causes immune deficiency and sometimes even death faster. Viruses that replicate faster and require more selenium atoms like Ebola, or that infect more types of cells, like SARS-CoV-2, can kill more rapidly.

Because RBCs lack a nucleus and the cellular machinery needed to produce proteins, viruses do not infect RBCs. However, besides iron, RBCs also require an adequate selenium supply. Low selenium levels cause anemia because RBCs need selenium to develop properly. Unlike iron-deficiency anemia, selenium-deficiency anemia has not been widely recognized by the medical profession. This may be due to the belief until 1967 that selenium is a poison. Due to the lingering effect of that archaic misunderstanding, not enough research has been conducted on selenium and anemia. Thus, although anemia is frequently treated by iron supplementation, only about 45% of anemias are responsive to extra iron. (5) Research is urgently needed to test selenium supplements against this common disease symptom because despite its probable benefit, selenium is not generally recognized as a treatment for anemia. That is because selenium has never been adequately studied against anemia in randomized, controlled clinical trials. It took an AIDS clinical trial conducted by a Harvard University researcher and the Nigerian Institute of Medical Research to reluctantly, and only partially reveal just how hugely beneficial selenium can be against HIV-related anemia. That result suggests it should help against other anemias too.

            Because both viruses and bacteria deplete the body’s selenium reserves, both can cause its deficiency. Selenium depletion reduces the amount available to form RBCs, so many viral, bacterial, and mycobacterial infections cause acute or chronic anemia, as in HIV disease. An abstract presented at the XVI International AIDS Conference in Montreal in 2006 reported the results of a Nigerian study of three antiretroviral (ARV) drugs alone, compared to those same three ARVs plus one standard 200mcg tablet of selenium. That clinical trial was conducted in advanced AIDS patients with an average of 50 CD4 count. After fifteen months the 170 patients who received the additional selenium tablet daily increased their CD4 count by 140% more than the increase in the 170 patients who received only three ARVs daily. Likewise, the group that received one extra selenium tablet per day demonstrated a 300% increase in RBC hemoglobin compared to a 100% increase in hemoglobin using the triple ARV combination therapy alone. (6) That clearly demonstrated not only the hugely significant benefit selenium provides boosting immunity by increasing critical CD4 white blood cells, but also the tremendous benefit selenium has against anemia. Why the medical community continues to ignore selenium as an adjunct therapy for both HIV disease and anemia is a mystery. This mystery deepens when one discovers that although the results of this well-organized, moderately large, controlled clinical trial showed dramatically positive results against both HIV and anemia, no scientific paper was ever published reporting those results – only a conference abstract poster. Thus, this extremely important scientific finding was lost to history. That resulted in worse health and shorter lives for millions in Africa and elsewhere who could have benefited from this impressive research breakthrough. One must question why the phenomenal results of this well-organized, randomized, double-blinded, controlled clinical trial were essentially covered up - hidden from future researchers, physicians, and the patients that knowledge could have helped.   

Anemia 

            Anemia is a common symptom of many diseases. It is a blood condition caused by a scarcity of red blood cells and the hemoglobin within them that transport oxygen. It results in less oxygen getting to the tissues and the fatigue that causes. Anemia can be acute, coming on quickly, or it can develop over time. It can be temporary or chronically long lasting; severe, or mild. The severity of anemia depends on the hemoglobin level. (5)

            Anemic symptoms vary depending on how quickly the disorder develops and how severe it is. When anemia develops slowly, symptoms include headache, breathlessness, fatigue, and muscle weakness. When onset is rapid symptoms include thirst, loss of consciousness, and confusion. Severe, chronic anemia, as in sickle cell disease, risks premature death. (5)      

            Many medical journal articles reference the influence of selenium on anemia. Journal article titles include “Association of serum selenium with anemia-related indictors and risk of anemia”(7), “Selenium deficiency as a risk factor for development of anemia”(8), Low serum selenium is associated with anemia among older adults”(9), Selenium deficiency and chronic anemia in an outpatient hematology clinic”(10), “Selenium deficiency is associated with anemia in heart failure patients”(11), “Macrocytic anemia induced by selenium deficiency in the course of anorexia nervosa”(12), and “Protective role of selenium against hemolytic anemia”(13). Yet if one Googles “treatments for anemia”, selenium supplementation is nowhere to be found. Why? Is this another medical mystery – that selenium not only has an effect causing anemia when levels are deficient, but it can help alleviate anemia when it is supplemented into the body? Is this gap in knowledge the result of a disconnect between science and modern medical practice - a disconnect that hurts not only all those who have anemia, but most critically, those who suffer from sickle cell disease? Surprisingly, reports of controlled clinical trials of selenium against various forms of anemia are virtually non-existent. This should be an active subject of scientific investigation. However apparently it is ignored because there is too little potential profit in testing cheap, safe, approved, existing therapies against health conditions selenium almost certainly will benefit against. Is there a solution that can bridge this chasm between the lack of solid clinical evidence and the practical, useful application of what is essentially known science? Yes, that bridge can be crossed by conducting randomized, controlled, clinical trials. Those would be relatively cheap to conduct, and millions would benefit. Why do we fail to conduct them?

            The scientific name for RBCs is erythrocytes. The physiological process of producing erythrocytes is called erythropoiesis. There are numerous medical journal articles with titles like “The regulation of erythropoiesis by selenium” (14), “The intricate role of selenium and selenoproteins in erythropoiesis” (15), and “Selenoproteins regulate stress erythroid progenitors and spleen microenvironments during stress erythropoiesis” (16). Given the titles of these articles, besides being a basic building block of RBCs, selenoproteins obviously play a crucial role in both the production and destruction of red blood cells/RBCs/erythrocytes.

            To simplify the scientific explanation in the first article referenced in the previous paragraph, just like in a fiery furnace, when RBCs are produced, they and the hemoglobin they carry are subjected to the highest degree of damaging oxidative stress. RBCs that contain less selenium are more subject to destruction and have a shorter life span. Higher bodily levels of selenium reduce the effect oxidative stress has in reducing the number of RBC precursor cells. Thus, higher selenium levels increase the number of progenitor/immature cells and that increases the number of mature RBCs. (14) Although red blood cells are normally produced in the marrow of large bones, when anemia exists, ancillary RBC generation takes place in the spleen. There erythropoietin (EPO) stimulates precursor cells to develop into mature RBCs. Higher selenium levels in the body improve the overall antioxidant environment. That increases EPO’s ability to stimulate RBC production and helps alleviate anemia. (14)

                In the journal Blood, Chang Liao explained that selenium deficiency is “a cofactor in the anemia associated with chronic inflammatory disease.”(16) Selenium deficiency is also a major factor in acute inflammatory conditions such as those caused by severe viral diseases including AIDS, Ebola, and Covid. Liao reasoned that “selenoproteins may contribute to [RBC] recovery from anemia”. His experiments showed that in anemia, selenium deficiency “severely impairs” the production of RBCs at two different points. Liao concludes that his experimental “data reveal a critical role of selenoproteins in the expansion and development of [RBC precursor cells] as well as the erythroid niche during acute anemia recovery.” (16)  

            Another article by Liao addresses how selenium affects the production of RBCs. It explains that the high levels of iron needed for production of RBCs causes high levels of oxidative stress. That stress has a negative impact on RBC development and can cause anemia. He explains that dietary selenium protects developing RBCs from damage but the lack of adequate selenium causes the destruction of RBCs due to oxidation. (15) His article relates that “selenium and selenoproteins have emerged to be crucial and beneficial to erythroid cells” and the production of RBCs and selenoproteins “are intricately involved in multiple ways” (15) with the overall selenium supply. Several selenium-based antioxidant proteins including Gpx1 and Txnrd2 exert critical roles in RBC development. Finally, Liao concludes that “In addition to redox regulation, selenoproteins appear to have a broader influence, which not only affects erythroid cell development at multiple stages, but also impacts the erythropoietic microenvironment.” (15) In laymen’s terms, the level of selenium in the body has a critical direct impact on the generation, maintenance, and lifespan of RBCs. One must question why this scientific knowledge is not mentioned in common public information sources like Wikipedia and is not used widely to treat SCD anemia, when even water – hydration - is recommended as a treatment. Why do we ignore the obvious – selenium?                

Sickle Cell Disease – SCD 

            There are more than a dozen causes and almost as many types of anemia. Anemias are caused by either a reduction in the production of new RBCs, an increase in the destruction of existing RBCs, or both. Sickle cell disease is caused when a person inherits the gene from both parents. That recessive genetic trait evolved to protect from frequently deadly mosquito borne malaria. The SC trait is protective when a person acquires it from only one parent. However, when a person inherits the gene from both parents it causes sickle cell disease. SCD does not protect against malaria. If a person with SCD contracts malaria, that causes a painful sickle cell crisis. (17)   

            Normal red blood cells are round, smooth, concave on both sides, and highly flexible so they can slip through narrow capillaries. Sickled RBCs are rigid, banana-shaped, and have sticky adhesion molecules protruding from them. Those three characteristics all contribute to their difficulty passing through narrow capillaries and to causing blood stoppages. When blockages occur, tissues are deprived of oxygen. That causes painful episodes that sometimes include micro-strokes and occasionally even more serious cerebral strokes. (17)

                Whereas normal RBCs have a life span of 90 to 120 days, due to their malformation, sickled cells are destroyed at a much faster pace and only survive for ten to twenty days. (17) Thus, a person with SCD is under pressure to produce new RBCs more rapidly. That requires improved nutrition, especially extra selenium. While RBCs are normally produced in the marrow of large bones, in people with anemia or hypoxia - lack of oxygen - production shifts to the spleen and increases to ten times the rate it is in the bone marrow.

            Sickle cell anemia causes a diversity of symptoms related to the blockage of blood and deprivation of oxygen. When significant blockages occur, they cause painful crisis episodes that usually last between five and seven days. Symptoms can include severe pain, swelling in the extremities, high blood pressure, stroke, chest pain, and bacterial infections. Those eventually result in long-term damage to the circulatory system, bones, and organs, as well as gallstones, blindness, irregular heartbeat, decreased immunity, heart problems, septic shock, stroke, and death. (17) Crisis episodes can be triggered by numerous events including stress, temperature change, injury, infection, dehydration, and high altitudes. However, often there is no obvious cause of a sickle cell crisis. Scientists have described various types of crises including vaso-occulusive crisis, splenic sequestration crisis, acute chest syndrome, aplastic crisis, and hemolytic crisis. Crises vary in how frequently they occur, how severe they are, and how long they last. Their frequency ranges from none to more than ten times per year. (17)

            The only cure for sickle cell disease is a compete bone marrow transplant. A newly developed gene-based therapy has been developed that supposedly completely cures the disease. This new gene therapy procedure costs between two and three million dollars and requires approximately two months hospitalization, a painful, total bone marrow transplant, and intensive chemotherapy. (18) Even though according to the Fred Hutch Cancer Reseaerch Center the fatality rate from complete bone marrow transplants has fallen from 30% to 11% in the past twenty-five years, this “cure” might not be for everyone. An array of other ad hoc therapies for symptomatic SCD includes pain killer NSAID drugs, steroids, opioids, L-glutamine, folic acid, hydration, penicillin, hydroxyurea, blood transfusion, voxelotor, and the monoclonal antibody crizanizumab. (17,19). Common sources of information like Wikipedia do not list selenium supplements as a treatment, although they should because selenium is essential to the development of all RBCs, it is an important component of all RBCs, and its level in the body affects the rate of both production and destruction of RBCs. Yet there is no report that selenium has ever been properly tested as a treatment for sickle cell anemia regardless of the fact it usually helps reduce many symptoms of SCD including inflammation, blood pressure, clotting, stroke, heart problems, shock, and organ damage. What do medical journals specifically report about selenium and SCD?         

            The earliest report of selenium deficiency in SCD patients may have been in 1990 when C.L. Natta reported that selenium levels were much lower in 20 SCD patients compared to 14 nonanemic control subjects. (20) In 1992 Toshi Kaneko reported that “oxidative damage of red cell membrane is known to be accelerated in sickle cell disease” and that selenium deficiency reduces protection against such damage. (21) A 2007 scientific review article pointed out that SCD patients had decreased antioxidant defenses. Reduced antioxidant protection increases stickiness between blood vessel and sickle cell (SC) adhesion molecules leading to clumping together with white blood cells and platelets. This clotting is what blocks capillaries and leads to kidneys, liver, heart, and brain damage. That is what causes most of the major problems in the disease and eventually premature death. The review article notes that SCD patients have higher numbers of white blood cells that produce twice as much pro-oxidant superoxide than they do in people who do not have SCD. The authors mention that SCD patients had low levels of antioxidant vitamins and selenium and that they would benefit from medications that inhibit the potent inflammatory transcription factor NF-kB. (22) Selenium inhibits NF-kB as do anti-inflammatory drugs that include, from weakest to more powerful – aspirin, ibuprofen, naproxen, sulfasalazine, diclofenac, resveratrol, curcumin, and dexamethasone. (23) The use of these and other anti-inflammatories should benefit against SCD, but the FDA has only specifically approved one, hydroxyurea. It seems odd that a dozen drugs of varying strengths inhibit NF-kB but only one is specifically “approved” for SCD. Of course, since selenium is the essential component of most cellular antioxidants, it should be one of the most powerful medications to treat SCD. Yet there is no evidence it even has been tested against SCD, only that it showed a surprisingly powerful effect against regular anemia in the Nigerian study that reported its benefits against advanced AIDS and AIDS-related anemia. Then that clinical evidence “disappeared” from science. Why?

            The above scientific review article points out that the inhibition of NF-kB by sulfasalazine reduces pro-oxidants and strongly decreases white blood cell adhesion/stickiness to capillaries, thus improving blood flow. (22) Other NSAID drugs and steroid anti-inflammatories should do so as well. This points to dexamethasone – the powerful steroid anti-inflammatory that was successively used to treat severe Covid as a potential drug to treat SCD crises. Finally, that 2007 medical journal review explains that the increased level of oxidative stress in SCD causes damage to the outer cellular membrane of SCs and contributes to their rigidity and early destruction. (22) I should note that, in general, selenium is known to improve blood flow and reduce clotting.     

            In a 2018 article in the journal Blood, the authors reiterate that “Oxidative stress in the RBCs of SCD patients may be elevated by lower levels of antioxidant proteins such as the selenium-dependent enzyme Gpx1 [glutathione peroxidase]. Gpx1 was first described as an enzyme capable of protecting hemoglobin from ROS [reactive oxygen species] and has been reported to be lower in RBCs in SCD. Selenium levels are lower in African Americans in the Chicago area and elsewhere.” “These results support the hypothesis that low selenium status likely results in reduced levels of antioxidant selenoproteins and enhanced SCD severity.” (24)

                In 2019 a Turkish researcher noted that both selenium and zinc were significantly lower in SCD patients compared to controls. He concluded, “Decreased blood levels of antioxidant trace elements may contribute to the pathophysiology in SCA by promoting oxidative stress.” He explained that “Low levels of glutathione peroxidase [Gpx1] among patients with SCA highlights the importance of selenium in handling the oxidative stress associated with SCA. In addition. Selenium has been shown to provide protection against oxidative stress-induced [cell damage] … among patients with SCA.” “Large scale studies are recommended.” (25) Here, I endorse his call to conduct long overdue, much needed clinical trial of selenium supplements against SCD.

            Scientists writing in the journal Nutrients reported “selenium deficiency and low selenium consumption….is the main determinant of hemolysis [RBC cell destruction] among the antioxidant nutrients analyzed. Thus, the data from that study suggests that the nutritional care protocols for patients with SCD should include dietary sources of selenium in order to reduce the risk of [RBC destruction].” (26) They continue by explaining that chronic RBC destruction that reduces RBC life by about 70% is a major feature of SCD. This accelerated cell death triggers a dramatic increase in pro-oxidants that, in a positive feedback loop, further damages sickle cells. “This process is cyclical and depletes the antioxidant systems, ultimately leading to oxidative stress.” The authors explain that selenium maintains the GPx “antioxidant enzyme, protecting hemoglobin against oxidation inside the [RBCs] thus making them less susceptible to hemolysis” [destruction]. “Additionally, selenium plays an important role during [red blood cell development], in which selenoproteins influence the multiple stages of [RBC] development ... Thus promoting adequate cell maturation.” (26) They explain that adequate selenium levels help protect RBCs from cell destruction or cell death and report that, “Positive associations between serum concentrations of selenium and [RBC] counts, hemoglobin level and hematocrit were observed” in SCD patients. “The other micronutrients did not present significant associations with hematological parameters.” The authors noted that most SCD patients had selenium deficient diets, had selenium deficiency, and this reduced their ability to produce new RBCs. They reported that in experiments, “Animals [lab rats] that received adequate amounts of selenium were able to recover from anemia, whereas maintenance of selenium deficiency was shown to be lethal.” They concluded that in SCD patients, selenium contributes to both an increase in the rate of RBC production and a decrease in the rate of RBC destruction. Finally, low levels of selenium “may aggravate the condition of [SCD] patients and result in more severe complications. An adequate selenium intake may probably improve SCD patients’ clinical status.” (26)

                Nigerian researchers reported that SCD “is the most common life-threatening genetic disorder worldwide” and that Nigeria has the highest SCD disease burden with 150,000 SCD births each year. In sub-Saharan Africa over 50% of infants born with SCD do not live to their fifth birthday. They explain that in their SCD blood analysis selenium was found to be very deficient (54.6ng/ml) in SCD patients versus (86.3ng/ml) in controls, and that “the selenium level decreases as the age increases.” They also report that “white blood count and platelet count was significantly higher among sickle cell disease subjects”. Additionally, they mention that the selenium deficiency caused by SCD “may contribute to development of a form of heart disease, hypothyroidism, and a weakened immune system.”  Finally, they reference another article that suggests that “Increasing evidence suggests that white blood cells (WBC), especially [larger] neutrophils, may be involved in the initiation and propagation of vaso-occulusive crisis in SCD.” (27)  

            A New Zealand scientist reported that of all the various comorbidities that contributed to mortality with Covid-19, patients with SCD suffered the highest rate of lethality. He reported that “SARS-CoV-2 may infect cells in the bone marrow, suppressing red blood cell formulation.” He stated that low levels of selenium were associated with higher levels of SC destruction, and higher levels of selenium increased SC RBC production. (28)

            With every report from the above scientists pointing towards selenium levels as the major factor influencing the production, maintenance, and destruction of sickle cell RBCs, it is exceedingly questionable why there have not been any large, double-blinded, controlled clinical trials of selenium against sickle cell anemia, despite logic and the numerous indications and calls by scientists to do so. This highlights a gaping defect in the American system of medical research that seeks first and foremost to develop new, expensive drugs against disease, while concurrently ignoring, and sometimes even covering-up safe, approved, available, affordable, existing medications that could be quickly, easily, and cheaply tested in randomized, controlled clinical trials to determine how effective they are in treating diseases that have harmed humanity for hundreds of years. Not only would results from these trials reduce the disease burden on Virginians, Americans, and people worldwide, they would also save money for insurance companies, government healthcare systems, and international health organizations.

            How long can state and national health authorities ignore this obvious, partial solution to an unusually painful, life-long, life-limiting disease? How much longer must people with SCD wait? The cost of using safe selenium tablets as complementary therapy for one year is approximately $40. The tragic failure to improve medical knowledge and life for people with SCD will continue until someone accepts the challenge to act to help humanity reduce the unnecessary disease burden this and other diseases impose on families, communities, and governments everywhere.                     

References

1.       Sickle Cell Virginia Organization SC-VA.org

2.       Center for Health Metrics and Evaluation      

3.       Center for Disease Control and Prevention – Data and Statistics on Sickle Cell Disease

4.       Wikipedia – Red Blood Cells

5.       Wikipedia – Anemia

6.       The role of selenium as adjunct to HAART among HIV-infected individuals who are advanced in their disease. NN Odunukwe et.al., abstract number MOAB0403, XVI International AIDS Conference, Montreal, 2006

7.       Association of serum selenium with anemia-related indicators and risk of anemia. Quin Zhou et.al., Food Science & Nutrition, 2021;9:3039-3047

8.       Selenium as a risk factor for the development of anemia. Tsvetelina V. Petkova-Marinova et.al., Journal of Biomedical Clinical Research 2017;10:1:9-17

9.       Low serum selenium is associated with anemia among older adults in the United States. RD Semba et.al., European Journal of Clinical Nutrition 2009;63:1:93-99

10.   Selenium deficiency and chronic anemia in an outpatient hematology clinic. Bryan Pham et.al., Blood 2023;142:Supplement1:5218

11.   Selenium deficiency is associated with anemia in heart failure patients – The HARVEST Study. J. Molvin et.al., European Heart Journal 2023;44:Supplement 2

12.   Macrocytic anemia induced by selenium deficiency in the course of anorexia nervosa: a case report:  R. Nishi et.al., Medicine 2023;102:51(e36740)

13.   Protective role of selenium against hemolytic anemia is mediated through redox modulation. Rankaljeet Kaur et.al., Biological Trace Element Research 2018;189:490-500

14.   The regulation of erythropoiesis by selenium in mice. Naveen Kaushal et.al., Antioxidants & Redox Signaling 2011;14:8:1403-1412

15.   The intricate role of selenium and selenoproteins in erythropoiesis. Chang Liao et.al., Free Radical Biological Medicine 2018; Nov.01:127:165-171

16.   Selenoproteins regulate stress erythroid progenitors and spleen microenvironments during stress erythropoiesis. Chang Liao et.al., Blood 2018;131:23:2568-2580

17.   Wikipedia – Sickle cell disease

18.   New sickle cell therapies will be out of reach where they are needed most, Rebeca Robbins and Stephanie Nolen, New York Times, December 8, 2023

19.   Sickle Cell Disease Treatment - National Institutes of Health, National Heart, Lung, and Blood Institute

20.   Selenium and glutathione peroxidase levels in sickle cell anemia. CL Natta et.al., Acta Haematology 1990;83:3:130-132

21.   Selenium, glutathione peroxidase and oxidative hemolysis in sickle cell disease. T. Toshio Kaneko, Acta Haematology 1992;87:105-106

22.   Sickle cell disease: role of reactive oxygen and nitrogen metabolites. Katherine C. Wood and D. Neil Granger, Clinical and Experimental Pharmacology and Physiology 2007;34:926-932

23.   Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kB activation, inhibition and expression of cyclooxygenase-2 and cyclin D1 and abrogation of tumor cell proliferation. Yasunari Takada et.al., Oncogene 2004;232:9247-9258

24.   The impact of selenium deficiency on a sickle cell disease mouse model, Ramasamy Jagadeeswaran et al., Blood 2018;132:Supplement1:3645

25.   Alteration in serum levels of copper, zinc, and selenium among children with sickle cell anemia. Rana Hasanato, Turkish Journal of Medical Sciences 2019;49:1287-1291

26.   Selenium status and hemolysis in sickle cell disease patients. Emilia Delesderrier et.al., Nutrients 2019;11:2211

27.   Some haematological parameters, copper, and selenium level among children of African descent with sickle cell disease in specialist hospital Sokoto, Nigeria. Osaro Erhabor et.al., Human Antibodies 2019;27:143-154

28.   Selenium supplementation may improve Covid-19 survival in sickle cell disease. George D. Henderson, British Journal of Nutrition 2021;128:4:778-779