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Literature Review & Commentary.

Iron Deficiency and Fibromyalgia

Eighty-one patients (mean age, 42.5 years) with fibromyalgia, a serum ferritin level below 50 ng/ml (mean, 18.6 ng/ml), and transferrin saturation below 20% (mean, 14.1%) were randomly assigned to receive, in double-blind fashion, intravenous ferric carboxymaltose (a form of iron) or placebo (normal saline), with the same treatment repeated five days later. The dose of each ferric carboxymaltose infusion was 15 mg per kg of body weight, up to a maximum 750 mg. The primary outcome measure was the proportion of patients who had at least a 13-point improvement in the Revised Fibromyalgia Impact Questionnaire (FIQR) score at six weeks after the first infusion. The proportion of patients who achieved the primary endpoint was higher in the iron group than in the placebo group (76.9% vs. 66.7%), but the difference was not statistically significant (p = 0.31). With respect to secondary endpoints, significantly greater improvements were seen in the iron group than in the placebo group for mean FIQR total score (p = 0.015), Brief Pain Inventory total score (p = 0.02), and Fatigue Visual Numeric Scale (p < 0.001).

Comment: Adenosine triphosphate (ATP) concentrations have been found to be low at sites of tenderness in patients with fibromyalgia, and it has been hypothesized that ATP deficiency plays a role in the pathogenesis of the disease. Iron is a cofactor for the enzyme, cytochrome oxidase, which plays a role in mitochondrial ATP production through the electron-transport chain. Consequently, iron deficiency might exacerbate symptoms in patients with fibromyalgia. In this study, treatment with iron improved symptoms in fibromyalgia patients who had low or borderline-low iron status. Although iron was given intravenously in this study, oral iron would probably be sufficient in most cases.

Boomershine CS, et al. A blinded, randomized, placebo-controlled study to investigate the efficacy and safety of ferric carboxymaltose in iron-deficient patients with fibromyalgia. Rheumatol Ther. 2018 5:271-281.

Vitamin D Deficiency and "Growing Pains"

Among 33 children (mean age, 9 years) in Italy who were experiencing "growing pains," the mean serum 25-hydroxyvitamin D (25[OH]D) level was 15.7 ng/ml. Nineteen children (57.6%) had a 25(OH)D level between 10 and 20 ng/ml, and 8 (24.2%) were below 10 ng/ml. Patients with 25(OH)D levels below 30 ng/ml received vitamin D supplementation for three months. The dosage was 25,000 IU orally once a month for levels between 20 and 30 ng/ml, 100,000 IU orally once a month for levels between 10 and 20 ng/ml, and 100,000 IU intramuscularly once a month for levels below 10 ng/ml. The mean 25(OH)D level increased from 15.7 ng/ml at baseline to 34.1 ng/ml at three months. Pain severity was assessed on a 10-point scale, with 0 indicating no pain and 10 indicating the worst pain. Mean severity of "growing pains" improved from 7.5 at baseline to 2.7 after three months. At 24 months, apparently with no additional vitamin D supplementation, the mean serum 25(OH)D level was 22.7 ng/ml and mean severity of growing pains was 3.9.

Comment: "Growing pains" is a term used to describe general muscle aches and pains that occur in children, most often in the legs. The term is probably a misnomer, as there is no firm evidence that the growth of bones causes pain. The pains are believed to be caused by excessive running, jumping, and other activity. Recommended treatments include massage, local heat, and analgesics.

Musculoskeletal pain is one of the manifestations of vitamin D deficiency. In an uncontrolled trial, vitamin D supplementation improved "growing pains" in Turkish children with a low serum 25(OH)D level. (1) The current study from Italy supports the observation that "growing pains" may be caused in part by vitamin D deficiency.

Morandi G, et al. Significant association among growing pains, vitamin D supplementation, and bone mineral status: results from a pilot cohort study. J Bone Miner Metab. 2015;33:201-206.

Adverse Effect of "Green Smoothie"

A 65-year-old woman with previously normal renal function developed acute oxalate nephropathy, which progressed to end-stage renal disease. One month previously she had undergone a 10-day juice fast, which included two cups per day of juiced spinach (about 10 times the oxalate content of a typical diet). The woman had two risk factors for hyperoxaluria: gastric bypass surgery (which increases oxalate absorption secondary to fat malabsorption) and prolonged antibiotic therapy three months previously for an abdominal wall abscess (antibiotic therapy can deplete oxalate-degrading bacteria in the intestinal tract).

Comment: Many people drink smoothies as a way of getting fruits, vegetables, yogurt, nuts, and other healthful items into their diet. Smoothies can be good for you, provided that they don't contain too much sugar or other unwanted ingredients. However, drinking smoothies or juices that contain large amounts of spinach or beet greens can result in excessive oxalate consumption, potentially leading to kidney stones or acute renal injury.

The woman in this case report had two known risk factors for hyperoxaluria. However, even in the absence of known risk factors, excessive oxalate consumption can, on rare occasions, have serious adverse effects. In another case report, an 81-year-old man developed acute renal failure, apparently from repeatedly consuming large amounts of juices that contained spinach and beet greens. (2) While advanced kidney disease is a known risk factor for oxalate-induced renal injury, this man had only mild chronic kidney disease, with an estimated glomerular filtration rate of 48 milliliters per minute. These case reports demonstrate that it is important to consider the oxalate content of juices and smoothies, and it is probably a good idea to go easy on the spinach and beet greens.

Makkapati S, et al. "Green smoothie cleanse" causing acute oxalate nephropathy. Am J Kidney Dis. 2018;71:281-286.

Selenium Supplements and Mortality

Four hundred ninety-one volunteers (aged 60-74 years) in Denmark were randomly assigned to receive, in double-blind fashion, 100, 200, or 300 [micro]g per day of selenium (as seleniumen-riched yeast) or placebo for five years, and were followed up for mortality for an additional 10 years. Selenium nutritional status in Denmark is considered to be moderately low, with usual dietary intake around 50 [micro]g per day. In intent-to-treat analysis, compared with placebo, the highest selenium dose (300 [micro]g per day) resulted in an approximately 60% increase in mortality, both at the end of the five-year supplementation period and 10 years later. This increase in mortality, though of similar magnitude at both time points, was not statistically significant after five years, but was significant after 15 years. In contrast, the 100 and 200 [micro]g per day doses resulted in nonsignificant decreases in mortality, compared with placebo, during the five-year supplementation period, with no clear effect 10 years after selenium was discontinued.

Comment: Selenium is among the most toxic of the essential minerals. Estimates of dietary selenium intake in the United States and Canada have ranged from 60 to 224 [micro]g per day. Adverse effects of excessive selenium intake include hair loss, brittleness or loss of the nails, white spots on the nails, dermatitis, lassitude, depression, and various neurological abnormalities. Toxicity has been observed in people consuming 3,200 [micro]g per day or more. Whether long-term use of doses closer to the amount found in the diet would have adverse effects has not been well studied.

The Food and Nutrition Board of the Institute of Medicine has set the Tolerable Upper Intake Level for selenium at 400 [micro]g per day. The Tolerable Upper Intake Level is defined as "the highest average daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population." However, based on the findings of the new study, it would appear unwise to recommend long-term supplementation with more than 200 [micro]g per day unless there is a clear medical reason to do so. In regions such as South Dakota, where the soil is high in selenium and dietary selenium intake is around 150-300 [micro]g per day, selenium supplementation should probably be avoided or used only in the low doses that might be found in a multivitamin-multimineral product.

Rayman MP, et al. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial. Free Radic Biol Med. 2018 Feb 14 [Epub ahead of print].

Another Advantage of Breast Milk

Infant rhesus macaques were either breastfed, fed a formula containing a low amount of lutein, or fed a formula supplemented with lutein to approximate the concentration in breast milk. At six months of age, compared with each formula-fed group, the breastfed group had markedly higher concentrations of lutein in serum, brain, retina, and liver. For example, the mean lutein concentration in the brain and macular portion of the retina was more than three times higher in animals fed breast milk than in those fed lutein-supplemented formula. Lutein concentrations were higher in most tissues in animals fed the supplemented formula than in those fed the unsupplemented formula. In all three groups, lutein was differentially distributed across brain areas, with the highest concentrations in the occipital cortex (which is involved in visual processing).

Comment: In this study in rhesus macaques, supplementation of infant formula with lutein significantly increased serum and tissue lutein concentrations compared with unsupplemented formula. However, lutein concentrations were still well below those of animals fed breast milk. With all three diets, occipital cortex had higher lutein concentrations than other brain regions, suggesting that lutein plays a role in visual processing early in life. This study demonstrates that breast milk contains a mechanism to enhance the delivery of lutein to the tissues and organs, which may be important for the development of the visual system. This effect, which cannot be duplicated by adding lutein to infant formula, represents another apparent advantage of breastfeeding over formula feeding.

Jeon S, et al. Lutein Is differentially deposited across brain regions following formula or breast feeding of infant rhesus macaques. J Nutr. 2018;148:31-39.

Probiotic for Dandruff

Sixty healthy male volunteers (aged 18-60 years) with moderate-to-severe dandruff were randomly assigned to receive, in double-blind fashion, Lactobacillus paracasei NCC 2461 ST11 ([10.sup.9] colony-forming units once a day) or placebo for eight weeks. The mean improvement in the free-dandruff score (70% vs. 23%; p = 0.0005), the adherent-dandruff score (72% vs. 34%; p = 0.0005), and in erythema (58% vs. 31%; p < 0.05) was significantly greater in the probiotic group than in the placebo group.

Comment: Dandruff is a persistent inflammatory condition of the scalp. Contributing factors include an imbalance in the proportion of the bacterial and fungal populations colonizing the scalp, skin barrier dysfunction, and excessive seborrhea. Probiotics have the potential to improve dandruff by altering the microbial environment of the scalp. In the present study, oral administration of a specific probiotic (Lactobacillus paracasei NCC 2461 ST11) was beneficial in the treatment of dandruff.

Two of the authors of the study were employees of Nestle (which supplied the probiotic), and three other authors were employees of L'Oreal (of which Nestle is part owner). While conflicts of interest do not necessarily invalidate the results of research, it is hoped that an independent research group will try to replicate this study.

Reygagne P, et al. The positive benefit of Lactobacillus paracasei NCC2461 ST11 in healthy volunteers with moderate to severe dandruff. Benef Microbes. 2017;8:671-680.

Probiotic Prevents Dental Caries

Two hundred sixty-one children (aged 2-3 years) attending a nursery school in Chile were randomly assigned to receive, in double-blind fashion, 150 ml of milk supplemented with Lactobacillus rhamnosus SP1 ([10.sup.7] colony-forming units per ml) or regular milk (control group) on weekdays for 10 months. The mean number of new dental caries was significantly lower by 35% in the probiotic group than in the control group (1.13 vs. 1.75; p< 0.05).

Comment: In previous studies, L. rhamnosus GG and L. reuteri DSM 17938 each reduced the incidence of dental caries in children. (3,4) The new study adds L. rhamnosus SP1 to the list of effective anti-caries probiotic strains. Probiotics may work in part by competing with cariogenic bacteria in the mouth, such as Streptococcus mutans.

Rodriguez G, et al. Probiotic compared with standard milk for high-caries children: a cluster randomized trial. J Dent Res. 2016;95:402-407.

Vitamin D for Dry Eye Syndrome

One hundred five South Korean patients (mean age, 58.2 years) with dry eye syndrome and vitamin D deficiency or insufficiency (mean serum 25-hydroxyvitamin D level, 10.5 ng/ml) received 200,000 IU of vitamin D3 intramuscularly. Patients with Sjogren's syndrome or other autoimmune diseases were excluded. Significant improvements were seen in the tear break-up time and tear secretion test after two and six weeks, and in eyelid margin hyperemia and severity of symptoms after two, six, and 10 weeks.

Comment: Some studies have found that dry eye syndrome (also called sicca syndrome or keratoconjunctivitis sicca) is associated with low serum 25-hydroxyvitamin D (25[OH] D) levels, although other studies were unable to confirm that finding. Serum 25(OH)D levels decline in response to inflammation, and in people with chronic inflammatory conditions such as dry eye syndrome, a low serum 25(OH) D level may not necessarily indicate vitamin D deficiency. In addition, dry eye syndrome has not been previously mentioned as a symptom of vitamin D deficiency. This study provides preliminary evidence that vitamin D supplementation improves dry eye syndrome in people with low serum 25(OH)D levels; however, the results need to be confirmed by a placebo-controlled trial.

Bae SH, et al. Vitamin D supplementation for patients with dry eye syndrome refractory to conventional treatment. Sci Rep. 2016;6:33083.


(1.) Vehapoglu A, et al. Are growing pains related to vitamin D deficiency? Efficacy of vitamin D therapy for resolution of symptoms. Med Princ Pract. 2015;24:332-338

(2.) Getting JE, et al. Oxalate nephropathy due to 'juicing': case report and review. Am J Med. 2013;126:768-772.

(3.) Nase L, et al. Effect of long-term consumption of a probiotic bacterium, Lactobacillus rhamnosus GG, in milk on dental caries and caries risk in children. Caries Res. 2001;35:412-420.

(4.) Stensson M, et al. Oral administration of Lactobacillus reuteri during the first year of life reduces caries prevalence in the primary dentition at 9 years of age. Caries Res. 2014;48:111-117.

by Alan R. Gaby, MD
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Title Annotation:nutrition-related medical conditions
Author:Gaby, Alan R.
Publication:Townsend Letter
Article Type:Report
Date:Nov 1, 2018
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