Benefits of Treatment with Hydroxyurea for Sickle Cell Disease Patients

This article is published as part of Nutri Inspector’s scholarship application by Grace Omotunde who studies the Nutrition Interventions, Communication,and Behavior Change program at the Friedman School of Nutrition Science and Policy at TuftsUniversity.

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Do the benefits of treatment with Hydroxyurea for Sickle Cell Disease patients outweigh the harmfulside effects of the drug?

Sickle Cell disease is a genetic disorder that alters the shape and function of red blood cells(RBCs). Under extreme heat or cold temperatures, dehydration, infections, or low oxygen (hypoxia)in the body, RBCs “sickle”, or form a crescent shape in a person who has the disease. Sickling causesmany symptoms, including pain crises, Acute Chest Syndrome, leg ulcers, organ damage or failure,stroke, and death. Consequently, physicians and researchers have searched for effective treatments toreduce symptoms and find cures. They recommend lifestyle changes (consuming healthy foods,engaging in moderate physical activity, taking supplements) as with any patient, but strongly advisethe use of a drug called Hydroxyurea. Present research findings suggest that Hydroxyurea helps toreduce severe Sickle Cell Disease symptoms. However, further investigation may be required tounderstand the long-term effects of the drug.

The genetics and mechanisms behind Sickle Cell Disease​

Sickle Cell Disease (SCD) is a condition with genotypes that differ in severity and in thepercentages of mutated (HbS), normal (HbA) or fetal (HbF) hemoglobin (Hb) present in the blood. The genotypes include sickle cell Hb C (HbSC), sickle cell Hb SE (HbSE), sickle cell thalassemia(S-β+thalassemia, sickle cell anemia-α thalassemia, and S-β0thalassemia) and sickle cell anemia(HbSS), in order of increasing severity [2, 3]. In SCD, a genetic missense mutation (a single basechange from adenine to thymine) in the β-hemoglobin gene (HBB) changes the amino acid sequencewhere valine is substituted for glutamate [1, 2]. The normal HbA β-globin chains are consequentlyreplaced with HbS β-globin chains [2].

Under deoxygenated conditions, HbS polymerizes from the hydrophobic interactions in thesickle Hb tetramers and causes sickling; under oxygenated conditions, however, the HbS polymerbreaks down and unsickles [1, 2]. The repetitive polymerization and depolymerization of the HbS β-globin chains damage the membrane cytoskeleton of the red blood cell (RBC) and eventually leads toirreversible sickling [1, 2]. Sickling also occurs under conditions of acidosis and intracellulardehydration, which increases mean cell hemoglobin concentration (MCHC); a higher MCHC favorssickling [1].

Fetal hemoglobin (HbF), on the other hand, reduces the rate and degree at which red bloodcells sickle [1]. Since Hydroxyurea induces HbF expression and production, it has become arecommended treatment for SCD. HbF works by inhibiting deoxygenated HbS from polymerizingand lowering the concentration of HbS, thereby decreasing sickled red blood cells [3, 4]. HbF levelsin individuals with SCD range from 2% to 5%. Physicians and researchers aim to increase thispercentage because the more that is present, the better.

Hydroxyurea and its use in Sickle Cell Disease​

Hydroxyurea (HU) is an antineoplastic drug (used to treat Leukemia, melanoma and othermyeloproliferative disorders) that increases the production of HbF and thus reduces RBC sicklingwhen used in patients with SCD [1, 2, 6]. Hydroxyurea may be of most benefit to patients withmoderate to severe SCD. HU increased HbF levels in one study to 20% – a significant increase sinceHbF levels can be as low as 2% in SCD [1, 2]. Additionally, researchers observe reduced pain crises, acute chest syndrome incidence, hospitalizations, and mortality after treatment with HU because ofits ability to increase HbF and decrease sickling, vaso-occlusion, and infarction [2].

Hydroxyurea relieves or reduces symptoms associated with SCD​

​Sickle Cell Disease can present many symptoms. Pain crises (also termed acute painfulepisodes/crises, bone pain crises, and vaso-occlusive crises) is not only the most common symptomof SCD, but is also the most frequent reason for ER visits [5, 6]. Pain crises vary in intensity and lastanywhere from a few hours to many days, yet many times the specific cause is unknown [1]. It is,however, understood that the following conditions can trigger a crisis: cold, dehydration, physicalexertion, infections such as the flu or malaria, tobacco smoke, alcohol use, hypoxic conditions, hotweather, emotional stress, high altitude, pregnancy, physical pain, or the onset of menses [1].

Pain crises result from tissue ischemia and infarction caused by blood vessel obstruction [5].Because most RBCs in SCD are sickled, their shape hinders RBC movement through blood vessels,particularly in smaller vessels. If enough sickled RBCs accumulate and obstruct blood flow, thisleads to pain in the affected area that sometimes spreads to other parts regions of the body.Hydroxyurea reduces pain crises by indirectly decreasing the amount of HbS that is responsible forcausing sickled cells – HU’s increase in HbF yields a decrease in HbS.

Hydroxyurea, along with chronic transfusion, has also been proven to be effective inreducing ACS incidence and recurrence [2, 6]. Acute Chest Syndrome (ACS) – another symptom ofSCD – is the most frequent cause of death and affects more than half of all sickle cell anemiapatients, especially those with sickle cell anemia [2, 6]. It results from vaso-occlusion of pulmonaryvessels and microbial involvement and is characterized by fever, chest pain, wheezing, cough,hypoxia, worsening anemia and a new lung infiltrate [1, 2, 6]. Additionally, pain crisis in the chestcan also trigger ACS as a result of pain induced hypoventilation, which encourages sickling in thepulmonary bed and microbial growth [1]. Since ACS results from RBC sickling and vaso-occlusion like pain crises, HU is beneficial in reducing ACS due to its role in inducing HbF expression andproduction.

Anemia is also characteristic of SCD and results from hemolysis of sickled RBCs (recallpermanent sickling causes membrane and cell structure damage) [2]. HU counters anemia byincreasing RBC production, and thus raising Hb levels [2, 3]. The degree to which HU helps increaseHb and RBC levels varies per patient; however, many studies have observed increases as high as inthe normal Hb range (12 and 18 g/dL) or more, in contrast to SCD Hb levels of 6 to 9 g/dL [1, 2].

Other treatments vs. Hydroxyurea​

Where a pain crisis may be tolerated at home, NSAIDS are often used to treat the pain.However, if hospitalization is required or the crisis lasts longer than 2 or 3 days, stronger analgesicsor opioids are then administered [1]. Treatment may also include use of heat in the pain area(s),blood transfusion, and saline to increase hydration and blood fluidity [1, 2]. NSAIDs come with theirown risks (i.e., kidney and liver failure) and excessive use of opioids can exacerbate or even causeAcute Chest Syndrome [1, 2, 4]. Additionally, NSAID and opioids do not prevent pain crises or ACSoccurrence.

Thus, for episodes of three or more per year, physicians require or strongly advisehydroxyurea therapy [11, 12, 13, 15]. One pain crisis alone can create tissue damage and otherdeleterious effects to the body, so the cumulative affects of three or more crises and/or a history ofAcute Chest Syndrome that can lead to CVD, stroke, or organ damage are of much concern tophysicians and researchers. HU has been found to reduce pain crises and ACS occurrences andphysicians believe the benefits far outweigh its transient side effects or toxicities [11, 12,13].

When administered, HU requires constant monitoring and correct titration since it can lead tocytopenias, which are a common side effect [6, 11, 12]. They were, however, mild and reversiblewith discontinuation or a decrease in hydroxyurea dose [12]. Additional side effects of HU includeskin and nail hyperpigmentation, headache, mild gastrointestinal symptoms, and leg ulcers [11, 12].

Of more concern is HU’s mutagenicity and teratogenicity since it inhibits DNA synthesis and thecell’s ability to correct mutated DNA. There have been some studies noting cancer incidence fromHU treatment in few patients with SCD, so these findings have made physicians and parents hesitantto use HU to treatment SCD [11, 12, 14, 15].

Nutrition as treatment for Sickle Cell Disease​

Nutritional researchers seek to find nutritional interventions that reduce SCD symptoms andelucidate nutrient deficiencies that have been linked to clinical features of SCD. Nutrient deficienciesmay result from a combination of factors, including food intake and micro- and macronutrientmechanisms in SCD [7]. The constant breakdown and regeneration of RBCs also increases themetabolic rate and nutritional needs beyond normal intake [7]. As a result, SCD patients tend to havedelayed height and weight gain (in children, but reach normal height in adulthood), impaired immunefunction, delayed menarche in female HbSS adolescents, all of which suggest the presence ofnutritional deficiencies [7]. Many physicians emphasize folate supplementation to support RBCformation and reduce possible folate deficiency. Studies have either shown some benefits in SCD,while others show uncertainty in folate’s efficacy. Folate supplementation has appeared to be mostadvantageous in cases where serum folate levels are very low; where folate levels were adequate,additional supplementation didn’t significantly increase its role in producing more RBCs to increaseHb levels and reduce anemia [7, 8, 10]. Nonetheless, folate supplementation remains as a form oftreatment to build RBCs.

Vitamin D Deficiency has recently emerged as an area of focus due to its high prevalence. Ithas been associated with decreased lung function, bone health, CVD, asthma, nephropathy, andchronic pain in those with SCD [9]. Some studies have shown that vitamin supplementation hasincreased serum vitamin D levels and decreased pain crises, while other studies require furtherresearch due to small sample sizes and some biases [9].

Because supplementation may not always drastically increase Hb levels or reduce diseasesymptoms as may be required, Hydroxyurea has become the focal point in SCD symptom preventionor reduction. Because HU appears to make significant improvements in those with SCD, it may bethe current best course of treatment, while vitamin supplementation may complement some of HU’sactions. The literature has not shown HU’s effects over the course of 10, 15, 20 years, or longer sinceit is a new therapy. It is with hope that researchers continue studies on this drug as well as onnutrition in SCD to gain better understanding of each form of treatment.


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