Osteopenia and vitamin D deficiency in children with sickle cell disease

Objectives: To assess the prevalence in children with sickle cell disease of low bone mineral density (BMD), a feature found in up to 82% of adults but not well known in children. Methods: In 53 children (45 SS, 4 SC, 4 Sβ‐thalassemia) with a mean age of 12.8 ± 2.4 years, we assessed height; weight; sexual maturation; number of hospitalizations, painful crises, and transfusions in the last 3 years; calcium intake; steady‐state hemoglobin and leukocyte count; calcaemia, phosphataemia, and calciuria/creatinuria; serum 25‐(OH)D and PTH concentrations; and osteocalcin, urinary deoxypyridinoline, and the C‐terminal component of pro‐collagen type I. BMD was assessed using dual X‐ray absorptiometry. Results: Mean lumbar spine Z‐score was ?1.1 ± 1.3 (?3.9 to +1.8). The Z score was significantly lower in girls than in boys in the prepubertal subgroup (?1.74 ± 0.27 vs. ?0.53 ± 0.31) (P = 0.0169), but not in the pubertal group (?1.15 ± 0.41 vs. ?1.33 ± 0.70). BMD was not associated with any of the disease‐severity markers in girls but was unexpectedly associated with fewer vaso‐occlusive crises and hospitalizations in boys. BMD did not correlate with hemoglobin or leukocyte counts. Vitamin D deficiency [25‐(OH)D < 12 ng/mL] was found in 76% of patients and secondary hyperparathyroidism (PTH > 46 pg/mL) in 38%. BMD was not related to calcium intake, vitamin D status, osteocalcin, or bone resorption markers. Conclusion: A slight BMD decrease was found in SCD children, starting before puberty and being more marked in females. The decrease was unrelated to disease severity, vitamin D deficiency, or bone hyperresorption, suggesting abnormal bone formation as the underlying mechanism.     

Optimization of folic acid, vitamin B(12), and vitamin B(6) supplements in pediatric patients with sickle cell disease

Using homocysteine as a functional marker, we determined optimal folic acid, vitamin B(12), and vitamin B(6) dosages in 21 pediatric sickle cell disease (SCD) patients (11 HbSS, 10 HbSC; 7-16 years). Daily supplements of folic acid (400, 700, or 1,000 microg), vitamin B(12) (1, 3, or 5 U.S. 1989 RDA), and vitamin B(6) (1 or 3 U.S. 1989 RDA) were gradually increased in an 82-week dose-escalation study. Blood was taken at 9 occasions for measurements of erythrocyte (RBC) and serum folate, plasma vitamin B(12), whole-blood vitamin B(6), and plasma homocysteine. Augmentation of folic acid from 700 to 1,000 microg and vitamin B(12) from 3 to 5 RDA did not further decrease homocysteine. Percentages of patients exhibiting significant individual homocysteine decreases amounted to 43% (folic acid from 0 to 400 microg, vitamins B(12) and B(6) from 0 to 1 RDA), 14% (folic acid from 400 to 700 microg), 24% (vitamin B(12) from 1 to 3 RDA), and 18% (vitamin B(6) from 1 to 3 RDA ). The lowest plasma homocysteine at 82 weeks was 5.9 +/- 2.2 micromol/L. Patients with HbSS had higher RBC folate than HbSC. The entire group exhibited an inverse relation between RBC folate and hemoglobin. We conclude that RBC folate is less valuable for folate status assessment in SCD patients. Optimal dosages are as follows: 700 microg folic acid (3.5-7 U.S. 1989 RDA), 3 U.S. 1989 RDA vitamin B(12) (4.2-6.0 microg), and 3 U.S. 1989 RDA vitamin B(6) (4.2-6.0 mg). A practical daily combination is 1 mg folic acid (4.3-8.5 U.S. 1998 RDA when taken with meals), 6 microg vitamin B(12) (2.5-5 U.S. 1998 RDA), and 6 mg vitamin B(6) (4.6-10 U.S. 1998 RDA). This combination may by simple and relatively inexpensive means reduce these patients' inherently high risk of endothelial damage.     

High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study

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.     

Diminished vitamin B12 levels in patients with severe sickle cell disease

Abstract. Objective. The aim of this study was to estimate the levels of vitamin B₁₂ in patients with severe sickle cell disease compared to normal controls. Complete blood count, iron studies and vitamin B₁₂ levels were obtained in 85 consecutive patients with severe sickle cell disease (56 males, 29 females, aged 14–49 years) and 100 healthy blood donors (67 males, 33 females, aged 17–60 years) as a normal control group. Results. Thirty-seven of the 85 patients (43.5%) had serum vitamin B₁₂ levels below normal values (mean 84.3 ± 28.7, range 7–145 pmol L^?1) without macrocytosis or hypersegmented neutrophils. The mean level of vitamin B₁₂ in the remaining 48 patients (56.5%) was normal (mean 233.3 ± 73.9, range 152–435 pmol L^?1) which is below the mean of normal control levels (mean 327.7 ± 168.7, range 178–897 pmol L^?1). Patients with low B₁₂ achieved a significant symptomatic improvement when treated with vitamin B₁₂, 1 mg intramuscularly weekly for 12 weeks when compared with patients with normal B₁₂ levels. Conclusion. We conclude that many patients with severe sickle cell disease may suffer from unrecognized vitamin B₁₂ deficiency.     

维生素D缺乏与非骨骼疾病关系的研究进展

近年来的研究发现,维生素D不仅在骨骼疾病中发挥重要作用,在非骨骼疾病中也具有非常重要的作用。基础研究证实,维生素D受体广泛分布于体内各种组织细胞;临床研究发现,补充维生素D对预防和治疗代谢综合征及心血管疾病、自身免疫性疾病以及肿瘤有重要作用。本文就维生素D缺乏与上述疾病关系的研究进展进行综述。     

Nutrition and sickle cell disease

The role of protein and calorie deficiency in sickle cell disease remains poorly defined. While such features as growth retardation, impaired immune function, and delayed menarche do suggest a relationship between sickle cell disease and undernutrition, measurement of more direct nutritional parameters in these patients have yielded mixed results. Anthropometric measurements such as skinfold thickness are subnormal in many but not all reports. Serum protein levels are normal, but low values for serum lipids have been reported. Finally, one small study shows an improvement in both growth parameters and clinical course following caloric supplementation. A variety of micronutrient deficiencies have been suggested in sickle cell disease. Numerous case reports describing an exacerbation of the chronic anemia that was reversed by folic acid therapy led to routine folate supplementation. More recent studies have shown, however, that clinically significant folic acid deficiency occurs only in a small minority of sickle cell patients. Clearly, more work is necessary to define the cost/benefit ratio of routine folic acid supplementation. Pharmacological amounts of vitamin B6 and certain of its derivatives possess in vitro antisickling activities. Nevertheless, a small clinical trial failed to demonstrate any consistent hematologic effects of B6 supplementation. Several reports indicate that vitamin E levels are low in sickle erythrocytes. Since these abnormal red cells both generate excessive oxidation products and are more sensitive to oxidant stress, and because oxidants appear to play a role in ISC formation, vitamin E deficiency could well be linked to ISC formation and hemolysis. Small clinical trials, however, have again failed to produce a clear hematological response in sickle cell anemia. The role of zinc in sickle cell disease has received considerable attention. Though studies are generally small, most do support a relationship between sickle cell disease and zinc deficiency. Etiologic associations between zinc deficiency and such complications of sickle cell disease as poor ulcer healing, growth retardation, delays in sexual development, immune deficiencies, and high ISC counts have all been suggested. Most of these studies need further corroboration. Iron deficiency is now known to be a relatively common occurrence in sickle cell anemia, especially in children and pregnant women. The theoretical benefits of concomitant iron deficiency and sickle cell anemia remain to be proven in a controlled clinical trial.(ABSTRACT TRUNCATED AT 400 WORDS)     

Medical care utilization and mortality in sickle cell disease: a population-based study

The purpose of this study was to evaluate the pattern of medical care utilization and mortality in children and adults with sickle cell disease (SCD) in the state of Tennessee. Rates of hospitalization, emergency department visits, and deaths were measured in a cohort of adults and children with SCD enrolled in TennCare, Tennessee's Medicaid managed health care program, from January 1995 to December 2002. TennCare data linked to Tennessee vital records were used to define the population and identify the outcomes. For children less than 5 years of age, the mortality rate was similar to that of other black Tennessee children (P = 0.71). Among children, the death rate was highest in 10-19 years of age and was 8-fold higher than Tennessee's race- and age-specific rate. Among 20- to 49-year-old patients with SCD, mortality was significantly higher in males than in females (P < 0.001). As compared to the black population without SCD in TennCare, patients with SCD had 7-30 times higher rate of hospitalization and 2-6 times higher rates of emergency department visits (P < 0.001). The death rate in adolescents and young adults with SCD continues to be much higher than population-specific rates. Interventions to prevent morbidity and mortality related to SCD are urgently needed.     

Causes of death in sickle cell disease: an autopsy study

More precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality in sickle cell disease. In this study, the morphological evidence of the cause of death was studied in 306 autopsies of sickle cell disease, which were accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33-48%). The terminal infection was heralded by upper respiratory tract syndromes in 72.6% and by gastroenteritis in 13.7%. The most frequent portal of entry in children was the respiratory tract but, in adults, a site of severe chronic organ injury. Other causes of death included stroke 9.8%, therapy complications 7.0%, splenic sequestration 6.6%, pulmonary emboli/thrombi 4.9%, renal failure 4.1%, pulmonary hypertension 2.9%, hepatic failure 0.8%, massive haemolysis/red cell aplasia 0.4% and left ventricular failure 0.4%. Death was frequently sudden and unexpected (40.8%) or occurred within 24 h after presentation (28.4%), and was usually associated with acute events (63.3%). This study shows that the first 24 h after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. Close monitoring and prompt aggressive treatment are warranted.     

Emerging therapies in sickle cell disease

Despite sickle cell disease (SCD) being the most common and severe inherited condition worldwide, therapeutic options are limited. To date, hydroxyurea remains the main treatment option in SCD. However, in the last decade the numbers of interventional clinical trials focussing on therapies for SCD have increased significantly. Many new drugs with various pharmacological targets have emerged and, although the majority have failed to show benefit in clinical trials, some have produced encouraging results. It seems probable that more drugs will soon become available for the treatment of SCD. Furthermore, promising clinical trials with improved outcomes have recently changed the perspective of curative therapies in SCD. Nevertheless, the application of novel therapeutic agents and potential curative treatments will most likely be limited to high-income countries and, thus, will remain unavailable for the majority of people with SCD in the foreseeable future.     

维生素D缺乏与高血压相关研究进展

维生素D是一种脂溶性维生素,目前已知其在调节骨骼代谢、钙盐平衡方面起着重要的作用。近年来,虽然许多研究者发现高血压患者中维生素D缺乏的发生率很高,维生素D缺乏可能导致高血压的发生、发展,但是补充维生素D与高血压的研究结果不一致。因此文章就维生素D缺乏与高血压的相关研究进展作一综述。     

Vitamin E correlates inversely with non-transferrin-bound iron in sickle cell disease

Decreased serum vitamin E levels are found in homozygous sickle cell disease (SCD). Excessive transfusions may lead high non-transferrin-bound iron (NTBI). Hypothesizing a relationship between the two, vitamin E (measured using high performance liquid chromatography) was significantly lower in 30 SCD patients than in 30 age-/sex-matched controls (P < 0.001), but NTBI (bleomycin assay) was higher (P < 0.001). Vitamin E was lower in 10 transfused patients than in 20 non-transfused patients (P < 0.001) with a significant inverse correlation between the NTBI and vitamin E (r = -0.58, P < 0.001). NTBI associated with iron overload in SCD may increase the potential for oxidative damage and low vitamin E activity may compound this effect.     

Intracranial 4D flow magnetic resonance imaging reveals altered haemodynamics in sickle cell disease

Stroke risk in children with sickle cell disease (SCD) is currently assessed with routine transcranial Doppler ultrasound (TCD) measurements of blood velocity in the Circle of Willis (CoW). However, there is currently no biomarker with proven prognostic value in adult patients. Four‐dimensional (4D) flow magnetic resonance imaging (MRI) may improve risk profiling based on intracranial haemodynamics. We conducted neurovascular 4D flow MRI and blood sampling in 69 SCD patients [median age 15 years (interquartile range, IQR: 12–50)] and 14 healthy controls [median age 21 years (IQR: 18–43)]. We measured velocity, flow, lumen area and endothelial shear stress (ESS) in the CoW. SCD patients had lower haematocrit and viscosity, and higher velocity, flow and lumen area, with lower ESS compared to healthy controls. We observed significant age‐related decline in haemodynamic 4D flow parameters; velocity (Spearman's ρ = −0·36 to −0·61), flow (ρ = −0·26 to −0·52) and ESS (ρ = −0·14 to −0·54) in SCD patients. Further analysis in only adults showed that velocity values were similar in SCD patients compared to healthy controls, but that the additional 4D flow parameters, flow and lumen area, were higher, and ESS lower, in the SCD group. Our data suggest that 4D flow MRI may identify adult patients with an increased stroke risk more accurately than current TCD‐based velocity.     

Fetal haemoglobin induction in sickle cell disease

Fetal haemoglobin (HbF, α2γ2) induction has long been an area of investigation, as it is known to ameliorate the clinical complications of sickle cell disease (SCD). Progress in identifying novel HbF‐inducing strategies has been stymied by limited understanding of gamma (γ)–globin regulation. Genome‐wide association studies (GWAS) have identified variants in BCL11A and HBS1L‐MYB that are associated with HbF levels. Functional studies have established the roles of BCL11A, MYB, and KLF1 in γ–globin regulation, but this information has not yielded new pharmacological agents. Several drugs are under investigation in clinical trials as HbF‐inducing agents, but hydroxycarbamide remains the only widely used pharmacologic therapy for SCD. Autologous transplant of edited haematopoietic stem cells holds promise as a cure for SCD, either through HbF induction or correction of the causative mutation, but several technical and safety hurdles must be overcome before this therapy can be offered widely, and pharmacological therapies are still needed.     

DNA hypo-methylating agents and sickle cell disease

Fetal haemoglobin (HbF, alpha2) decreases polymerization of sickle haemoglobin (HbS) and high levels correlate with decreased morbidity and mortality in sickle cell disease (SSD). Therefore, a therapeutic goal in SSD is the pharmacologic reactivation of HbF. Silencing of the globin (HbF) gene is associated with DNA methylation. The cytosine analogues 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine) hypomethylate DNA by inhibiting DNA methyl-transferase. In clinical trials, 5-azacytidine and decitabine have demonstrated the greatest efficacy in HbF reactivation. Clinical development of these drugs has been delayed by concerns regarding the carcinogenic potential of 5-azacytidine. Furthermore, controversy regarding DNA hypomethylation versus more generic cytotoxic effects as the mechanism of action suggested that other cytotoxic/cytostatic agents might be as effective. Additional preclinical data and clinical studies of decitabine have tempered many safety concerns and have confirmed that DNA hypomethylation is the mechanism of action. Pharmacologic reactivation of HbF through DNA hypomethylation holds promise as an effective disease modifying intervention for patients with SSD. Larger studies are required to confirm safety and effectiveness with chronic use.     

多发孤立性浆细胞瘤伴维生素D缺乏

多发孤立性浆细胞瘤(MSP)发病率低,相关报道罕见。本文报道1例63岁女性患者,右下肢针刺样疼痛2月余,伴麻木、乏力。实验室检查提示高甲状旁腺激素血症,血清骨源性碱性磷酸酶升高,维生素D缺乏。神经肌电图显示右下肢神经源性损害。骶椎、骨盆CT增强提示骶1椎体右侧见软组织团片灶,呈膨胀性骨质破坏,骨皮质破裂。18 F-FDF PET/CT显示胸骨、胸、腰椎椎体、左侧髂骨及右侧骶骨骨质破坏影。CT引导下经皮穿刺活检免疫组化显示浆细胞骨髓瘤、CD138(+)、MUM-1(+)、Lambda(+)。结合骨髓涂片等结果该病例诊断为多发孤立性浆细胞瘤。