Description of the condition
Sickle cell disease (SCD) is an inherited chronic hemolytic and pro-inflammatory disorder that affects over 100,000 people in the USA and millions around the globe (Ashley-Koch 2000; CDC 2012b; Weatherall DJ). The disease is most commonly found in sub-Saharan Africa as well as in the Mediterranean basin, Saudi Arabia, Central America and India. In some African countries, the prevalence of the sickle gene in the population ranges from less than 1% to as high as 45% (WHO 2010). The clinical manifestations of SCD result from the presence of mutations on the beta globin genes that generate an abnormal hemoglobin product (called hemoglobin S) within the red blood cell (WHO 2010). During periods of hypoxemia and deoxygenation, a conformational change occurs in the sickle hemoglobin that results in the deformation of red blood cells into a 'sickle' shape. Downstream effects of this include increased vascular adhesivity that leads to vaso-occlusion and exaggerated hemolysis, which in turn leads to a chronic anemia. There are several genotypic variants that comprise the range of disorders referred to as SCD. The most common and perhaps most clinically severe form, is sickle cell anemia (homozygous SS disease), which results from the inheritance of two abnormal sickle S genes. The co-inheritance of two different abnormal beta globin genes (one being the sickle S gene) results in the various subtypes of SCD. Common subtypes of SCD include haemoglobin SC disease (co-inheritance of one sickle S gene and an abnormal haemoglobin (C) gene) (CDC 2012a) and haemoglobin Sβ+/0 thalassaemia (co-inheritance of the sickle S genes (S) with an abnormal beta thalassemia gene) (Rees 2010).
Pain and musculoskeletal complications are the most common reason for health care utilization among people with SCD and remains an important cause of acute and chronic morbidity (Almeida 2005). Acute bone complications such as painful vaso-occlusive crisis, osteomyelitis, stress fractures, orbital compression syndrome, vertebral collapse and bone marrow necrosis are common in patients with SCD. Chronic bone complications such as osteonecrosis, chronic degenerative arthritis, osteoporosis, compression spine deformities, dental gnathopathy and impaired growth are also common (Almeida 2005). Individuals with SCD suffer acute and chronic end-organ damage secondary to recurrent episodes of vaso-occlusion and chronic ongoing hemolysis. Acute complications not related to bones include strokes, splenic and hepatic sequestration, acute chest syndrome, priapism and aplastic crisis. Chronic end-organ damage in SCD may present as sickle nephropathy, retinopathy, leg ulcers, pulmonary hypertension and chronic endocrinopathies (Kato 2007). In addition, SCD patients are at greater risk of bacterial infection (Ramakrishnan 2010) which contributes to early mortality (Platt 1994).
Individuals with SCD suffer global deficits in energy and nutrients intake (Hyacinth 2010; Kawchak 2007), with increased catabolism that ultimately causes multiple macro- and micro-nutritional deficiencies (Hyacinth 2010). Among the micronutrient deficiencies, vitamin D deficiency has been found to be extremely common in people with SCD, regardless of age and season (Rovner 2008). The prevalence of vitamin D deficiency among individuals with SCD ranges from 33% to 100% (Adewoye 2008; Buison 2004; Goodman 2010; Gorrido 2012; Jackson 2012; Rovner 2008). Since vitamin D regulates the absorption and excretion of calcium and is essential for bone mineralization (AFMC 2009), its deficiency in SCD patients may contribute to the myriad of musculoskeletal health problems encountered. These include muscle weakness, chronic debilitating bone pain, avascular necrosis, bone fragility and compression fractures (Osunkwo 2011), which in turn can lead to functional impairment in mobility and interfere in education, employment and psychosocial development (Swanson 2011).
Description of the intervention
Sources of vitamin D include skin exposure to ultraviolet B radiation in sunlight, dietary sources such as oily fish and variably fortified food, and supplementation (Kennel 2010; Pramyothin 2012). There are two important forms of vitamin D: calciferol (ergocalciferol) (vitamin D2); and cholecalciferol (vitamin D3), which are both biologically inert form (Holick 2007; Kennel 2010; Park 2011). Vitamin D is metabolized in the liver to 25-hydroxyvitamin D (25(OH)D) which is the major form circulating in the blood stream (Chung 2009; Pramyothin 2012). Subsequently, the 25-hydroxyvitamin D (25(OH)D) is metabolized into its active form 1,25-dihydroxyvitamin D (1,25(OH)2D), mainly in the kidney and some other organs such as the colon, prostate and mammary gland, etc by the action of the 1 α-hydroxylase enzyme.
The primary functions of vitamin D are to maintain calcium homeostasis and support bone health (Gonzalez 2010; Kennel 2010). Vitamin D affects the calcium and phosphorous absorption in the intestine and indirectly affects bone mineralization by maintaining normal calcium and phosphorous concentration in the blood. Moreover, vitamin D has extra-skeletal effects on other systems such as the cardiovascular, immune and pancreatic systems, as well as on muscles, on the brain and on the control of cell cycles (Chung 2009; Gonzalez 2010; Holick 2006). The daily requirements of vitamin D recommended by the USA's Institute of Medicine (IOM) (Ross 2011) and the US Endocrine Practice Guidelines Committee (Holick 2011; Pramyothin 2012) are described as follows.
|Life-stage group (both sexes)||IOM|
Committee recommendations for
patients at risk for vitamin D deficiency
|0 to 12 months||400 to 1000 IU|
|1 to 18 years||400 IU||600 IU||600 to 1000 IU|
|19 to 70 years||400 IU||600 IU||1500 to 2000 IU|
|over 70 years||400 IU||800 IU||1500 to 2000 IU|
EAR: estimated average requirement; RDA: recommended dietary allowance
Vitamin D supplementation is usually safe and its toxicity is very rare; however, prolonged periods of excessive intake of vitamin D may result in malaise, drowsiness, nausea, vomiting, abdominal pain, thirst, constipation and loss of appetite (Bennett 2003; Park 2011). It can also lead to hypercalcaemia and causes confusion, cardiac arrhythmias, renal failure and coma (Bennett 2003).
How the intervention might work
The role of vitamin D in calcium homeostasis and bone health has been recognized for many years (Holick 2007; Kennel 2010). Recent studies have also shown that vitamin D has a role in the prevention of cancer (e.g. prostate, colorectal, breast, and pancreas), heart disease, fractures and falls, periodontal disease, autoimmune disease, respiratory infections (e.g. tuberculosis, influenza), type 2 diabetes and depression (Bischoff-Ferrari 2006; Chung 2009; Gonzalez 2010). In SCD, vitamin D supplementation can normalize the serum 25-hydroxyvitamin D (25(OH)D), which not only improves bone health and bone mineral density (Adewoye 2008), but also reduces chronic pain and improves quality of life (Osunkwo 2012). Moreover, vitamin D is also important for the immune system (Hewison 1992) for fighting infectious diseases (Chung 2009; Gonzalez 2010). Supplementing vitamin D in SCD patients may reduce the respiratory complications that can contribute to early mortality (Ramakrishnan 2010).
Why it is important to do this review
Vitamin D supplementation is relatively simple as both vitamin D2 and D3 supplements are easily available (Kennel 2010). The empirical evidence shows the importance of vitamin D on bone mineralization and musculoskeletal health. Moreover, numerous studies suggest that vitamin D plays a role in many chronic diseases (Bischoff-Ferrari 2006; Chung 2009; Gonzalez 2010; Holick 2007) and in supporting the immune system (Hewison 1992). Cochrane systematic reviews of randomised controlled trials have been carried out on the effect of vitamin D supplementation in other conditions (Avenell 2009; Bjelakovic 2011; Ferguson 2012; Jagannath 2010; Palmer 2009a; Palmer 2009b; Straube 2010; Winzenberg 2010). However, the effect of vitamin D supplementation in SCD has never been reviewed. It is therefore important to determine the effects of supplementing vitamin D in order to reduce complications that contribute to significant morbidity and mortality in people with SCD.