Overview Sickle Cell and Vitamin D

 
Several Sickle Cell trials have found that a loading dose of vitamin D followed by a good sized maintenance dose greatly reduces the number of days of SC pain

• The size of the loading and maintence doses should vary by weight and health.
• One study used a loading dose 100,000 IU weekly for 6 weeks - ignoring weight
• One study used a loading dose of 5,234 IU/kg for 4 days
• Perhaps $10 of Vitamin D per year can substantially reduce the $14,700 a year cost of Sickle Cell

See also VitaminDWiki

• Vitamin D should be an almost universal feature of the care of young adults with sickle cell disease – May 2018
• Search VitaminDWiki for "sickle cell" 215 web pages contained the phrase as of Jan 2024
• Off topic: Malaria recovery associated with having more immature red blood cells – Sept 2016
• Overview Dark Skin and Vitamin D
• Do blacks have a 5 year life penalty due to low vitamin D
• Diabetes (Type 1) 14X more likely in dark skin children with low levels of vitamin D – May 2015
  • example of increased diseases in dark-skinned children
• 26 health factors increase the risk of COVID-19 – all are proxies for low vitamin D
  • CDC list of high-risks for COVID-19 includes Sickle Cell
• 5X more likely to be vitamin D deficient if anemic - Dec 2012
  • Independent of Sickle Cell
• Low vitamin D - anemia 2.2X more likely (no surprise) – meta-analysis Aug 2015
• Overview Pain and Vitamin D
  • perhaps one of the reasons that Vitamin D helps with SC is by pain reduction

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9+ VitaminDWiki pages have SICKLE in the title

This list is automatically updated

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Overview Loading of vitamin D contains the following

Loading dose: 211 studies at VitaminDWiki

Vitamin D loading dose (stoss therapy) proven to improve health overview
If a person is or is suspected to be, very vitamin D deficient a loading dose should be given

• Loading = restore = quick replacement by 1 or more doses
• Loading doses range in total size from 100,000 IU to 1,000,000 IU of Vitamin D3
  • = 2.5 to 25 milligrams
• The size of the loading dose is a function of body weight - see below
  • Unfortunately, some doctors persist in using Vitamin D2 instead of D3
• Loading may be done as quickly as a single day (Stoss), to as slowly as 3 months.
  • It appears that spreading the loading dose over 4+ days is slightly better if speed is not essential
• Loading is typically oral, but can be Injection (I.M,) and Topical
• Loading dose is ~3X faster if done topically or swished inside of the mouth
  • Skips the slow process of stomach and intestine, and might even skip liver and Kidney as well
• The loading dose persists in the body for 1 - 3 months
  • The loading dose should be followed up with on-going maintenance dosing
  • Unfortunately, many doctors fail to follow-up with the maintenance dosing.
• About 1 in 300 people have some form of a mild allergic reaction to vitamin D supplements, including loading doses
  • it appears prudent to test with a small amount of vitamin D before giving a loading dose
  • The causes of a mild allergic reaction appear to be: (in order of occurrence)
  • 1) lack of magnesium - which can be easily added
  • 2) allergy to capsule contents - oil, additives (powder does not appear to cause any reaction)
  • 3) allergy to the tiny amount of D3 itself (allergy to wool) ( alternate: D3 made from plants )
  • 4) allergy of the gut to Vitamin D - alternative = topical

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16 Items in both categories of Bone Health and Dark Skin (a proxy for Sickle Cell)

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Monthly Vitamin D (100K, 150K, 200K IU) improved health of sickle cell children in many ways - Aug 2024

Safety and efficacy of monthly high-dose vitamin D3 supplementation in children and adolescents with sickle cell disease
Eur J Pediatr. 2024 Aug;183(8):3347-3357. doi: 10.1007/s00431-024-05572-w
Diana Hanna 1, Doaa E Kamal 2, Hebatallah M Fawzy 3, Reham Abd Elkhalek 4

Average of 30 ng after 6 monthly doses

Little is known about the impact of vitamin D supplementation on hand grip strength (HGS) and health-related quality of life (HRQoL) in children and adolescents with sickle cell disease (SCD). We aimed to evaluate the safety and efficacy of monthly high-dose vitamin D3 supplementation and its implications on bone mineral density (BMD), HGS, and HRQoL in patients with SCD and healthy controls.
The study included 42 children with SCD and 42 healthy matched controls.
The study participants were supplemented with high-dose monthly oral vitamin D3. Changes in the serum level of 25(OH) vitamin D3, maximum HGS, and BMD from baseline to 6 months were assessed, and the HRQoL questionnaire and Childhood Health Assessment Questionnaire (CHAQ) were used to evaluate the functional capacity. At baseline, SCD subjects had poorer growth status indicated by negative Z scores. Suboptimal BMD was detected by significantly lower Z score, and lower HGS and worse HRQL parameters were found compared to the controls (P < 0.001). Median 25(OH) vitamin D3 was significantly lower in SCD patients compared to controls (16.5 vs. 28 ng/mL, respectively (P < 0.001)). After 6 months of vitamin D supplementation, there was significant improvement in the DEXA Z-score (P < 0.001), limitation of physical health (P = 0.02), pain scores (P < 0.001), and CHAQ grades (P = 0.01) in SCD patients. A significant improvement in HGS (P < 0.001 and P = 0.005) as well as the CHAQ score (P < 0.001 and P = 0.003) was detected in the SCD group and controls, respectively.
There were no reported clinical adverse events (AEs) or new concomitant medications (CMs) during the study duration, and safe levels of Ca and 25 (OH) D3 were observed at 3 and 6 months for both groups. There was a significant positive correlation between HGS and total physical score (r = 0.831, P < 0.001) and a negative correlation with CHAQ score (r = - 0.685, P < 0.001). We also detected a significant positive correlation between vitamin D levels at 6 months and HGS (r = 0.584, P < 0.001), pain score (r = 0.446, P < 0.001), and a negative correlation with CHAQ score (r = - 0.399, P < 0.001).

Conclusion: Monthly oral high-dose vitamin D supplementation was safe and effective in improving vitamin D levels, HGS, and HRQoL in SCD children and healthy subjects, and BMD scores in SCD patients. Further randomized controlled trials are warranted to assess an optimal dosing strategy and to investigate the impact on clinically significant outcomes in children and adolescents with SCD and their healthy counterparts.
What is known:

• Several studies have reported a high prevalence of vitamin D deficiency and suboptimal bone mineral density (BMD) in sickle cell disease (SCD) patients.
• Musculoskeletal dysfunction is reported in SCD patients with a negative impact on physical activity and health-related quality of life (HRQL).
• Little is known regarding the impact of vitamin D3 supplementation in children and adolescents with SCD.

What is new:

• We found that monthly oral high-dose vitamin D3 supplementation was safe, tolerated, and effective in improving serum vitamin D levels, HGS, BMD scores, and HRQL in SCD patients.

Clipped from PDF
monthly oral vitamin D3 doses according to the baseline status of vitamin D as follows:

• sufficient: 100,000 IU,
• insufficient: 150,000 IU, and
• defcient: 200,000 IU

 Download the PDF from VitaminDWiki

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Expect better results if 1) dose varied by weight, 2) had used gut-friendly vitamin D, 3) started with loading dose

The average for the study was only 32 ng.
So about 40% did not have suffieince levels
Suspect that average could have been >50 ng if 1+2+3

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Nigeria is the Sickle Cell captial of the world - might Vitamin D help them?

Many of the residents have a gene that was modified to fight malaria
If both members of a couple have the poor gene, there is a 25% chance that their child will have Sickle Cell

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Sickle cell patients often have poor digestion (need gut-friendly vitamin D)

51% had diagnosed digestive disease problems
Digestives diseases associated to sickle cell anemia in Lubumbashi: epidemiological and clinical aspects - July 2019
PDF in French
Results: out of a total of 403 medical records examined we found 206 cases (n=206) of sickle cell disease associated with digestive disease, accounting for a rate of 51,11% of patients with sickle cell disease who suffered from digestive diseases. Both sexes were represented with a slight female predominance (51.94%) and a sex ratio M/F of 0.92. The most represented age ranges 1-6 years (32.52%), the average age was 11.8 years; the standard deviation was 21.9; the extreme ages were 13 months and 38 years. The reason for consultation was dominated by fever (60,67%), abdominal pain (44.66%) and digestive disorders (30,09%). Vaso-occlusive abdominal crises were found in 65 patients (31.55%) among whom 36 had only 1 crisis, 24 had 2 crises and 5 had 3 crises. Intestinal diseases were found in 121 patients (69,41%) dominated by intestinal parasites (found in 58 patients whose collection of stool samples showed 4 parasites: Yersinia enterocolitis, Entamoeba histolytica, Giardia intestinalis and Clostridium difficile). Gastric diseases were found in 105 patients ( 50,97%) divided into peptic ulcer (45 patients) and gastritis (60 patients); biliary vesicular disease was found in 40 patients (19.41%) including vesicular lithiasis without cholecystitis (32 patients), lithiasic cholecystitis (5 patients) and lithiasis in the main biliary tract (3 cases); there was 1 single case diagnosed with acute pancreatitis. The most common associated diseases in our study were respiratory diseases (169 cases;82,03%), oto-rhino-laryngological diseases (157 cases;76.21%), bony, vaso-occlusive crises (146 cases; 70,87%), urogenital diseases (64 cases; 31.06%) and malaria (51 patients; 24.75%). Hepatic diseases and diseases of the spleen were found in 18 cases (8.73%) and 47 cases (22,81%) respectively. Ultrasound was requested in 79 patients but only 31 of them underwent it because of the lack of financial means (it costs 20 U.S. dollars). In the case of clinically obvious splenomegaly, the search for Howell-Jolly bodies was requested in 23 patients but it was only performed in 2 patients because it costs 10 U.S. dollars). Routine blood count, hemoglobin, hematocrit, inflammatory assessment and thick drop examination were performed in all our patients but liver assessment, tests done on stool samples, urine test were recommended based on patient's complaint. Out of 206 patients, only 60 were under hydroxyurea treatment (29,16%).

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Sickle cell + 4 days of 5,234 IU/kg of vitamin D ==> not deficient - Dec 2014

Vitamin D deficiency and its correction in children with sickle cell anemia.
Ann Hematol. 2014 Dec;93(12):2051-6. doi: 10.1007/s00277-014-2144-7
Wykes C1, Arasaretnam A, O'Driscoll S, Farnham L, Moniz C, Rees DC.
1Department of Paediatric Haematology, King's College Hospital, King's College London, Denmark Hill, London, SE5 9RS, UK.

Vitamin D deficiency is common in sickle cell anemia (SCA, HbSS), although its significance and optimal means of correction are unknown. We conducted an audit to assess the clinical significance of 25-hydroxy vitamin D (25-OHD) deficiency in children with SCA and to evaluate two methods of vitamin D supplementation. We audited 25-OHD levels in 81 children with SCA and looked for statistical associations with biochemical, hematological and clinical parameters. In a separate group of regularly transfused children with SCA, we compared changes in 25-OHD blood concentrations following treatment with either high-dose intramuscular ergocalciferol (n = 15) or 4 days of high-dose oral cholecalciferol (n = 64). Ninety-one percent of children with SCA had 25-OHD levels <20 μg/L. The 25-OHD levels were negatively correlated with increasing age (P < 0.001) but showed no significant relationship to laboratory measurements, transcranial Doppler velocities or hospital attendance. Both intramuscular ergocalciferol and oral cholecalciferol supplementations resulted in increases of 25-OHD blood concentration to normal levels. The mean dose of ergocalciferol was greater than that of cholecalciferol (7,729 versus 5,234 international units (IU)/kg, P < 0.001), but the increment in 25-OHD levels was significantly greater in the oral cholecalciferol group (6.44 versus 2.82 (ng/L)/(IU/kg), P < 0.001).
Both approaches resulted in vitamin D sufficiency for about 120 days.
Increased 25-OHD concentration was significantly associated with increased serum calcium concentration. Vitamin D deficiency is very common in SCA and can be effectively corrected with high-dose intramuscular ergocalciferol or 4 days of high-dose oral cholecalciferol. Prospective, randomized studies are needed to assess the clinical value of vitamin D supplementation.
 Download the PDF from Sci-Hub via VitaminDWiki

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Prevalence of Vitamin D Deficiency in Sickle Cell Disease: A Systematic Review

PLOS One March 3, 2015DOI: 10.1371/journal.pone.0119908
Vikki G. Nolan , Kerri A. Nottage, Elliott W. Cole, Jane S. Hankins, James G. Gurney
Prevalence of Vitamin D Deficiency in Sickle Cell Disease: A Systematic Review
Vikki G. Nolan, Kerri A. Nottage, Elliott W. Cole, Jane S. Hankins, James G. Gurney PLOS x

Vitamin D deficiency has emerged as a public health focus in recent years and patients with sickle cell disease (SCD) reportedly have a high prevalence of the condition. Our objectives were to summarize definitions of vitamin D deficiency and insufficiency used in the literature, and to determine the prevalence and magnitude of each in patients with SCD through a systematic review conducted according to PRISMA guidelines. From a PubMed search, 34 potential articles were identified and 15 met eligibility criteria for inclusion. Definitions of deficiency and insufficiency varied greatly across studies making direct comparisons difficult. This review provides evidence to suggest that suboptimal vitamin D levels are highly prevalent among those with SCD, far more so than in comparable non-SCD patients or matched control populations.
Defining deficiency as vitamin D <20ng/mL, prevalence estimates in SCD populations range from 56.4% to 96.4%.
When compared with results from the population-based National Health and Nutrition Examination Survey, however, the general African American population appeared to have a similarly high prevalence of vitamin D deficiency. African American patients with and without SCD were both substantially higher than that of Caucasians. What remains to be determined is whether there are adverse health effects for patients with SCD because of concurrent vitamin D deficiency.

Discussion (from the PDF)
Vitamin D deficiency is one of the most common nutritional conditions among persons with SCD [2,25,26] and there are characteristics specific to SCD that may contribute to this phenomenon including decreased appetite [27,28], inability to absorb nutrients due to damage to the intestinal mucosa [29,30], as well as an increased basal metabolic rate and higher nutritional demands to sustain normal physiologic functioning [31–39]. Vitamin D deficiency has been associated with bone health [5,6], cardiovascular disease [7–9], asthma [10–12], nephropathy [1,13], and chronic pain [14–19] and individuals with SCD are susceptible to all of these complications [20–24]. While the role of vitamin D deficiency as a contributing factor in these complications is unclear, vitamin D deficiency can be reliably and inexpensively treated, making it a prime intervention to potentially improve health outcomes among those with SCD.
 Download the PDF from VitaminDWiki

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Diseases associated with Sickle Cell (and low vitamin D)

Vitamin D deficiency and comorbidities in children with sickle cell anemia.
Pediatr Hematol Oncol. 2012 Apr;29(3):261-6. doi: 10.3109/08880018.2012.661034.
Jackson TC1, Krauss MJ, Debaun MR, Strunk RC, Arbeláez AM.
1Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri, USA.

Vitamin D deficiency is known to be common among patients with sickle cell anemia (SCA). Vitamin D levels were measured in 139 children (aged 7.9 to 15.1 years) to study its association with SCA morbidities; severe deficiency <10 ng/mL was present in 64.0% and only 2.2% were sufficient (>30 ng/mL). Vitamin D levels were associated with pulmonary function (forced expiratory volume in 1 second [FEV(1)]), but not associated with either rates of acute pain or acute chest syndrome episodes. Further studies are needed to be able to compare outcomes in those with deficiency to those with sufficiency, as well as to treating patients with SCA with vitamin D to better establish a possible link, if any, between vitamin D and SCA morbidity.
 Download the PDF from VitaminDWiki

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Sickle Cell pain reduced for 6 months by 100,000 IU vitamin D weekly for 6 weeks - Oct 2015

Note by VitaminDWik - Loading dose can only be expected to last for 2-3 months, not 6 months
High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double-blind pilot study.
Br J Haematol. 2012 Oct;159(2):211-5. doi: 10.1111/bjh.12019. Epub 2012 Aug 28.
Osunkwo I1, Ziegler TR, Alvarez J, McCracken C, Cherry K, Osunkwo CE, Ofori-Acquah SF, Ghosh S, Ogunbobode A, Rhodes J, Eckman JR, Dampier C, Tangpricha V.
1Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, 1405 Clifton Road NE, Atlanta, GA 30322, USA. ify.osunkwo at choa.org
Far fewer days of pain between visits until Vitamin D loading dose wore off

We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were given a 6-week course of oral high-dose cholecalciferol (4000-100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82·5% and 52·5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects.
 Download the PDF from VitaminDWiki

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Global Burden of Sickle Cell Anaemia in Children under Five, 2010–2050

PLOS One July 2013 - the word vitamin does not occur in the PDF
 Download the PDF from VitaminDWiki

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Very low levels of vitamin D in Sickle Cell Patients, lower than just dark skin - March 2017

Vitamin D Deficiency in Adult Sickle Cell Patients
Journal of National Medical Association, Spring 2017Volume 109, Issue 1, Pages 36–43
The study just observes the association - but makes no comment about cause ==> effect
 Download the PDF from VitaminDWiki

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Sickle Cell events dropped from 4 per year to 1.5 yer year by monthly 100,000 IU - RCT May 2018

Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease.
Blood Adv. 2018 May 8;2(9):969-978. doi: 10.1182/bloodadvances.2017013979.
Lee MT1, Kattan M2, Fennoy I3, Arpadi SM4,5, Miller RL6,7, Cremers S8, McMahon DJ8, Nieves JW5, Brittenham GM1.
 Download the PDF from VitaminDWiki

Reduction in SC events

In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.
Note by the founder of VitaminDWiki
Would have gotten a much better response if any of the following:
1) Had used a gut-friendly form of vitamin D - about 40% increased response
2) Had dosed bi-weekly instead of monthly - about 20% increased response
3) Had taken the dose just before or during the largest meal of the day - about 30% increased response

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See also web

• Vitamin D supplementation for sickle cell disease Cochraine Jan 2017
  No conclusion could be made, studies had poor quality
  Free PDF for patients/caregivers, otherwise $38
• Vitamin D in children and adolescents with sickle cell disease: an integrative review July 2015
  "In 6 of the 11 studies, serum levels of vitamin D in children and/or adolescents with sickle-cell anemia were low."
   Download the PDF from VitaminDWiki
• CDC US
  SCD affects 90,000 to 100,000 Americans.
  SCD occurs among about 1 out of every 500 Black or African-American births.
  Costs in 2005:for SCD children: averaged $11,702 with Medicaid, $14,772 for children with employer-sponsored insurance.
• Sickle Cell Wikipedia
  "Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain ("sickle-cell crisis"), anemia, swelling in the hands and feet, bacterial infections, and stroke"
  "As of 2013 about 3.2 million people have sickle-cell disease while an additional 43 million have sickle-cell trait" US?
• Vitamin D Deficiency and Its Association with Inflammatory Markers, Lipid Profile and Regulatory T-cells in Pediatric Sickle Cell Disease Patients Oct 2017
  Publisher wants $40 for PDF. Nice abstract and references are free however

Quick summary of SC problems (Image from the web)