Literature Review and Commentary

by Alan R. Gaby, MD

Gluten Sensitivity in Fibromyalgia

Of 104 patients with both fibromyalgia and irritable bowel syndrome, 7 (6.7%) had celiac disease, as demonstrated by HLA-DQ2/HLA-DQ8 positivity, tissue transglutaminase antibodies, and duodenal biopsy. The 7 patients with celiac disease went on a gluten-free diet and experienced marked improvement in both their digestive and systemic symptoms.

In a second study, 20 patients with fibromyalgia (17 of whom also had irritable bowel syndrome or another gastrointestinal disorder), who did not have celiac disease (as demonstrated by tissue transglutaminase antibody testing, HLA typing, and absence of villous atrophy on duodenal biopsy) but who had had intraepithelial lymphocytosis on duodenal biopsy improved when placed on a gluten-free diet. The improvements were maintained during follow-up periods ranging from 5 to 31 months (mean, 16 months). Improvement was seen in some patients after a few months on the diet, whereas others required many months to see improvement. Clinical response was defined as 1 or more of the following: remission of pain, return to work, return to normal life, or discontinuation of opioids. These 20 patients were selected from a group of 246 patients with fibromyalgia, of whom 90 had a positive response to a gluten-free diet.

Comment

: The results of these 2 studies suggest that celiac disease is relatively common in people who suffer from both fibromyalgia and irritable bowel syndrome, and that in patients with celiac disease both the gastrointestinal symptoms and the fibromyalgia improve on a gluten-free diet. In addition, in more than one-third of fibromyalgia patients who do not have celiac disease, gluten sensitivity appears to contribute to the fibromyalgia. Based on these findings, patients with the combination of fibromyalgia and irritable bowel syndrome should be tested for celiac disease. Moreover, a trial of gluten avoidance should be considered for all patients with fibromyalgia.

Rodrigo L et al. Remarkable prevalence of coeliac disease in patients with irritable bowel syndrome plus fibromyalgia in comparison with those with isolated irritable bowel syndrome: a case-finding study. Arthritis Res Ther. 2013;15:R201.

Isasi C et al. Fibromyalgia and non-celiac gluten sensitivity: a description with remission of fibromyalgia. Rheumatol Int. 2014;34:1607–1612.

Monosodium Glutamate Triggers Fibromyalgia Symptoms

Fifty-seven patients (aged 18–75 years) who had both fibromyalgia and irritable bowel syndrome removed monosodium glutamate (MSG) and aspartame from their diet for 4 weeks. Thirty-seven patients completed the diet, and 84% of those 37 patients reported that more than 30% of their symptoms had resolved (responders). The responders were randomly assigned to a 2-week double-blind, placebo-controlled crossover challenge with MSG or placebo for 3 consecutive days each week. For each daily challenge, patients received 5 g of MSG in juice or the same juice without MSG. Compared with placebo, the MSG challenge resulted in a significant return of symptoms (p < 0.02 for total symptom score), a worsening of fibromyalgia severity as determined by the Fibromyalgia Impact Questionnaire-Revised (p < 0.03), and decreased quality of life with respect to IBS symptoms (p < 0.05).

In a second study, 72 women with fibromyalgia were randomly assigned to discontinue aspartame and MSG or to a waiting list control group for 3 months. There was no mention of how many of the women also had irritable bowel syndrome. Compared with the control group, there was no significant decrease in pain in the active-treatment group.

Comment

: MSG and aspartame act as excitatory neurotransmitters (excitotoxins), which have the potential to damage neurons and cause symptoms in susceptible individuals. Anecdotal evidence and case reports suggest that each of these compounds can trigger or exacerbate symptoms in people with fibromyalgia. The results of the 2 studies described above are conflicting, but they are consistent with the possibility that MSG sensitivity is a contributing factor in some patients with fibromyalgia, possibly only those who also have irritable bowel syndrome. A trial of avoiding MSG and aspartame for a few months has little downside, and is potentially beneficial.

Holton KF et al. The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms. Clin Exp Rheumatol. 2012;30(6 Suppl 74):10–17.

Vellisca MY, Latorre JI. Monosodium glutamate and aspartame in perceived pain in fibromyalgia. Rheumatol Int. 2014;34:1011–1013.

Coenzyme Q10 for fibromyalgia

Twenty patients with fibromyalgia were randomly assigned to receive, in double-blind fashion, 300 mg per day of coenzyme Q10 (CoQ10) or placebo for 40 days. Compared with baseline, the CoQ10 group showed a 52% improvement in the mean Fibromyalgia Impact Questionnaire score (p < 0.001), a 52% reduction in pain (p < 0.001), a 44% decrease in fatigue (p < 0.01), and a 44% reduction in the number of tender points (p < 0.01). There were smaller improvements in the placebo group, which were not statistically significant, but it was not clear whether the changes in the CoQ10 group were significantly greater than those in the placebo group.

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. As a cofactor in the electron-transport chain, CoQ10 plays an essential role in ATP production. The mean concentration of CoQ10 in salivary cells and blood mononuclear cells was significantly lower in patients with fibromyalgia than in healthy controls, which suggests that these patients may have suboptimal intracellular CoQ10 concentrations. The results of the present study suggest that CoQ10 can relieve symptoms in patients with fibromyalgia. However, because it was not clear whether CoQ10 was significantly more effective than placebo, the findings cannot be considered definitive.

Cordero MD et al. Can coenzyme Q10 improve clinical and molecular parameters in fibromyalgia? Antioxid Redox Signal. 2013;19:1356–1361.

Vitamin D Decreases Pain in Women with Fibromyalgia

Forty-two women with fibromyalgia and a serum 25-hydroxyvitamin D (25[OH]D) level below 32 ng/ml (mean, 20 ng/ml) were randomly assigned to receive, in double-blind fashion, vitamin D3 or placebo for 24 weeks. The initial dose was 2400 IU per day if the serum 25(OH)D level was less than 24 ng/ml and 1,200 IU per day if the level was 24 to 32 ng/ml. Serum 25(OH)D was measured after 4 and 12 weeks, and the dosage of vitamin D was adjusted to achieve a target 25(OH)D level of 32 to 48 ng/ml. Supplementation was stopped if the 25(OH)D level was above 48 ng/ml. The patients were evaluated at the end of the treatment period and again 24 weeks after treatment was stopped. Thirty women (mean age, 48 years) completed the trial. Treatment was stopped after 12 weeks in 47% of the women receiving vitamin D, because of elevated 25(OH)D levels; 12 weeks after vitamin D was stopped the mean 25(OH)D level in that group was 48 ng/ml. Compared with placebo, vitamin D significantly decreased pain severity (p = 0.03), but had no significant effect on the Fibromyalgia Impact Questionnaire.

Comment

: Muscle pain that can mimic fibromyalgia is one of the manifestations of vitamin D deficiency. The results of the present study suggest that vitamin D supplementation can decrease pain in women with fibromyalgia and a mean baseline 25(OH)D level of 20 ng/ml. Further research is needed to determine whether vitamin D would be beneficial for patients with higher 25(OH)D levels.

Wepner F et al. Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled trial. Pain. 2014;155:261–268.

Borderline-Low Iron Status in the Absence of Anemia Can Cause Fatigue

One hundred ninety-eight women (aged 18–53 years) with fatigue, a serum ferritin level less than 50 µg/L, and a hemoglobin level greater than 12.0 g/dl were randomly assigned to receive, in double-blind fashion, 80 mg per day of iron in the form of prolonged-release ferrous sulfate or placebo for 12 weeks. The mean score on the Current and Past Psychological Scale for fatigue decreased (improved) by 47.7% in the iron group and by 28.8% in the placebo group (p = 0.02 for the difference in the change between groups). At 12 weeks, compared with placebo, iron supplementation increased the mean hemoglobin level by 0.32 g/dl (p = 0.002) and the mean ferritin concentration by (11.4 µg/L; p < 0.001).

Comment

: Iron is a component of hemoglobin, which delivers oxygen to the tissues. In addition, iron is a cofactor for the enzyme, cytochrome oxidase, which plays a role in mitochondrial ATP production via the electron-transport chain. ATP is essential for nearly all energy-dependent processes in the body. Consequently, iron deficiency might be capable of causing fatigue even in people who are not anemic. The results of the present study suggest that iron supplementation is beneficial for some women with unexplained fatigue who have ferritin levels below 50 µg/L. Although a ferritin level of 50 µg/L is within the normal range, it may be a suboptimal level for some women.

Vaucher P, Druais PL, Waldvogel S, Favrat B. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ. 2012;184:1247–1254.

Which Intravenous Iron Preparation Is Safest?

A retrospective review was conducted on 688,183 Medicare patients who received intravenous iron from 2002 to 2013. Two hundred seventy-four episodes of anaphylaxis occurred during the first treatment, and an additional 170 episodes occurred during subsequent treatments. The risk of anaphylaxis during the first exposure to intravenous iron was 68 per 100,000 persons for iron dextran and 24 per 100,000 persons for all nondextran intravenous iron products combined (iron sucrose, gluconate, and ferumoxytol). At first exposure, when compared with iron sucrose, the adjusted odds of anaphylaxis for iron dextran was 3.6; for iron gluconate, 2.0; and for ferumoxytol, 2.2. The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons) and lowest with iron sucrose (21 per 100,000 persons).

Comment

: Intravenous iron therapy is becoming increasingly popular, because many iron-deficient patients (such as those with Crohn’s disease, other gastrointestinal disorders, or congestive heart failure) either fail to respond adequately to oral iron or experience intolerable side effects from it. Intravenous iron can correct iron deficiency rapidly and effectively, and it is usually well tolerated. However, all intravenous iron preparations carry a small risk of anaphylaxis. The results of the present study indicate that the risk of anaphylaxis is highest with iron dextran and lowest with iron sucrose.

Wang C et al. Comparative risk of anaphylactic reactions associated with intravenous iron products. JAMA. 2015;314:2062–2068.

Omega-3 Fatty Acids for Schizophrenia

Seventy-one patients (aged 16–35 years) hospitalized with a first episode of schizophrenia were randomly assigned to receive, in double-blind fashion, fish oil or placebo (olive oil) daily for 26 weeks, in addition to antipsychotic medication. The fish oil supplement provided daily 2.2 g of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid). The proportion of patients who had an improvement of at least 50% in symptom severity (as measured by the Positive and Negative Syndrome Scale) was significantly greater in the fish oil group than in the placebo group (69.4 vs. 40.0%; p < 0.02).

Comment

: Abnormally low concentrations of omega-3 fatty acids have been found in erythrocyte membranes of patients with schizophrenia. The results of the present study indicate that fish oil, when given as an adjunct to antipsychotic medication, improved outcomes in patients with new-onset schizophrenia. Other research has also found a positive effect of fish oil or the ethyl ester of eicosapentaenoic acid in patients with schizophrenia; however, some studies found no benefit. There is no clear explanation for the conflicting results in different studies. While additional research is needed to determine the optimal dosages and combinations of omega-3 fatty acids, as well as which patients are most likely to respond to treatment, a therapeutic trial of fish oil or omega-3 fatty acids would seem reasonable for selected patients with schizophrenia.

Pawełczyk T et al. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res. 2016;73:34–44.

Does This Household Chemical Promote Osteoporosis?

In a cross-sectional study of 1914 participants (mean age, 43 years) in the National Health and Nutritional Examination Survey 2009–2010, serum concentrations of perfluoroalkyl substances were inversely associated with bone mineral density, which varied according to the specific perfluoroalkyl substance examined and the bone site assessed. Most associations were limited to women.

Comment

: Perfluoroalkyl substances have been widely used in water- and stain-resistant coatings on clothing, nonstick housewares, and elsewhere for more than 60 years. They are ubiquitous environmental contaminants and are considered endocrine disrupters. While observational studies cannot prove causation, perfluoroalkyl substances should be investigated further as a potential cause of osteoporosis.

Khalil N et al. Association of perfluoroalkyl substances, bone mineral density, and osteoporosis in the U.S. population in NHANES 2009-2010. Environ Health Perspect. 2016;124:81–87.