Abstract
Everything in excess is opposed to nature…
Hippocrates 460-370BC
G
The “sunshine vitamin,” 1alpha,25-dihydroxyvitamin D (1,25(OH)2D), stimulates intestinal calcium absorption and regulates bone mineral metabolism;, therefore, being considered an important contributor to calcium and phosphorus homeostasis (3). Vitamin D (VitD), besides playing an important role in bone mineral metabolism, exerts endocrine actions on the cells of the immune system, generating anti-inflammatory and immunoregulatory effects. The 1-alpha hydroxylase enzyme converts 25-hydroxyvitamin (calcidiol) to the active form 1,25-dihydroxyvitamin D3 (calcitriol), which exerts its actions, mediated by the vitamin D receptor (VDR), throughout the organism (3). Although there have been conflicting results in different populations, an association between susceptibility to thyroid autoimmunity and VDR gene polymorphisms in GD (a significant increase in carriers of the rs7975232 allele A) was recently reported in a Chinese Han population, suggesting that the VDR gene might be one susceptibility gene that increases the risk of GD (4).
These results are possibly supported by those of another study conducted in Caucasians, with the primary aim of summarizing the evidence on the association between VDR gene polymorphisms and GD and, secondarily, with GO (5). This study indicated that the TT subtype of the TaqI polymorphism is likely to convey a higher susceptibility for GD than Tt and tt.
Serum VitD levels were found to be decreased in several autoimmune diseases, among many others, in GD, and particularly in patients with concomitant GO. A very recent study demonstrated that patients with GD, and especially smokers with high TRAb titers, had low levels of VitD, while immunological remission was more likely in nonsmokers who were treated with VitD (6). It was, therefore, suggested that VitD supplementation could potentially reduce the severity of disease activity in GD. This hypothesis was supported by the postulated increased risk of autoimmune diseases in states of VitD insufficiency. However, the mechanisms underlying the role of VitD in autoimmunity are not completely understood. Cells of the immune system (B cells, T cells, and antigen-presenting cells), in which the VDR and the 1α-hydroxylase (CYP27B1) are expressed, may synthesize VitD, which possesses immunomodulatory properties and plays a role in the regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) (7).
The first randomized prospective study to determine the effects of VitD on patients with GD was conducted in Japan (8) with 30 patients who were randomized to receive (a) antithyroid drugs (ATDs) in form of methimazole (MMI) alone or (b) concomitantly with 1.5 μg calcitriol daily for a period of 24 weeks. The group who received VitD together with MMI exhibited a higher decrease in rate of thyroid hormone levels and a higher increase in thyrotropin levels, whereas TRAb titers did not statistically differ between the two groups (8). However, still under debate are the optimal therapeutic dose and the plasma 25-hydroxyvitamin D concentration capable of possibly preventing or attenuating the clinical symptoms of autoimmune diseases, particularly of GD.
This issue of Thyroid includes a double-blinded clinical trial conducted by Grove-Laugesen et al. to investigate whether high-dose VitD supplementation in newly diagnosed GD patients may improve muscle activity and thyroid-related QoL (9). In total, 86 patients with GD, out of 348 who were screened, were randomly allocated to 9 months of treatment with 70 μg per day (2.800 IU) cholecalciferol (n = 44) or placebo (N = 42) in addition to ATD. At baseline and after 3 and 9 months of treatment, isometric muscle strength, muscle function tests, postural stability, body composition, and QoL were assessed. ATDs with placebo increased muscle force in all muscle groups investigated, whereas ATDs with VitD supplementation caused an attenuation of muscle strength increment, corresponding to a 23% lower rate of improvement than the placebo group. The increase in muscle force at handgrip and elbow flexion was 23% and 25% (p = 0.07), respectively, that is, smaller in the VitD group than in the placebo group. Although complaints of muscle weakness ceased in 21 subjects (50%) in the placebo group, this was reported in only 15 (34%) in the VitD group, while for force production and muscle function tests, no substantial effects of VitD supplementation were noted. For muscle strength at baseline, the authors observed a trend toward better QoL (lower QoL-impact score) and greater muscle strength.
The association of impaired daily life and muscle strength assessments was more pronounced in upper limbs strength, while regarding muscle strength at elbow flexion and extension, there was a statistically significant association with better QoL in terms of impaired daily life, tiredness, and the ThyPRO composite scale. However, an unexpectedly attenuated lean mass gain was observed. These results, underlining the importance of impaired muscle strength in the clinical assessment of GD and QoL and inversely, suggest that the diminished restoration of muscle activity in the VitD group may contribute to the lack of improvement of QoL after VitD treatment. It is also noteworthy that immunological parameters, such as TRAb levels, were not affected by the intervention. In contrast to other studies, the mean basal level of 25(OH)D was 67.3 ± 29.6 nmol/L; thus, it was not deficient and no statistically significant difference was found between the two groups. Supplementation with high-dose VitD increased 25(OH)D by 45 nmol/L, while it decreased in the placebo group by 14 nmol/L, resulting in a between-group difference of 59 nmol/L (p < 0.0001).
This well-designed study aimed to investigate, for the first time, the effects of high-dose VitD supplementation, administered concomitantly with ATD treatment, on muscle performance in GD over a period of nine months. One major finding was the unanticipated attenuation in muscle strength, in lean body mass gain, and in relatively low QoL improvement observed in the VitD-treated group. These results have partially been confirmed in a systematic review and meta-analysis of 30 controlled randomized studies, including >5600 non-GD patients, which showed that VitD supplementation, independent of the form and whether it was administered with or without calcium, has only a small positive impact on muscle strength (10); the article underscores the need for further studies to determine optimal treatment modalities and dose.
The other major finding of the Grove-Laugesen et al. trial was sex differences, a significant difference between women and men at knee extension (60 + 90) and knee flexion being noted, while among women, the same pattern of attenuation of muscle strength with VitD supplementation was found in all muscle groups, being, however, significant at hand grip and knee extension. Owing to the small number of males studied (n = 12), this group was not analyzed. The chief finding of this study is that high-dose VitD supplementation in GD was associated with moderately adverse rather than clearly beneficial effects, and that nine months after initiation of treatment, complaints, such as muscle pain and muscle weakness, were still present. The results of the study by Grove-Laugesen et al. concern only patients with hyperthyroidism, in which muscle protein wasting after protein degradation is a dominant characteristic. Nevertheless, the findings may also be of interest in the field of public health by increasing awareness as to optimum supplementation with VitD prescribed in the elderly with low basal levels of 25(OH)D, and particularly in those with frailty and nutritional deficiencies. This emphasizes the necessity for an additional therapeutic approach, besides ATD administration, in the treatment of GD. Supplemental VitD did not improve the increase in lean body mass achieved through ATDs as compared with placebo. In contrast, lean body mass tended to be lower at all sites in the VitD group, since the increase in subtotal lean body mass was 24% lower than in the placebo group (p = 0.08). While reduced lean body mass is consistent with the adverse effect of high VitD supplement on muscle performance and QoL in GD, the observed analogous nonsignificant effect of VitD on fat mass, body weight, and postural ability was of particular interest. Thus, the conclusion to be drawn is that high-dose VitD supplementation in GD lacks a clear benefit, though it does not demonstrate a significantly negative impact on most parameters.
The results of this study are partially corroborated by those of another investigation aiming primarily to evaluate whether daily VitD supplementation impacts GD recurrence (11). A total of 210 subjects with GD and VitD deficiency were recruited and monitored for at least 1 year after ATD discontinuation. Among the 210 patients, 60 (29%) were amenable to taking VitD supplements, resulting in sufficient VitD levels (from 10.6 to 25.7 ng/mL), whereas in the 150 patients who did not take VitD supplements, the mean VitD level was 11.6 ng/mL. However, patients with GD had lower VitD levels than the general population, though the VitD levels were not associated with the laboratory or clinical parameters of GD. Also, in this study, no difference in the recurrence rate was seen in the two groups (38% vs. 49%, p = 0.086) (11).
The study by Grove-Laugesen et al. generates a number of questions that require further investigation, particularly from the pathophysiological point of view. For instance, the differences in lean body mass gain in response to intervention, as compared with the placebo group, may partly account for the unexpected finding of attenuated muscle strength in the VitD group, which was associated with a lower score of QoL. One hypothesis might be that VitD deficiency increased the cytotoxicity mediated by radical oxygen species (ROS) (12), which can perpetuate ROS generation in hyperthyroidism and, thus, disruption of mitochondrial function. While VitD is likely to induce immunosuppression by enhancing Treg/T-17, the administration of high-dose VitD could oversaturate VDR activity, consequently attenuating the efficacy of VitD supplementation. Likewise, the potential presence of single nucleotide polymorphisms in the VDR gene (rs10735810; OR = 1.36 [CI 1.02–1.36], p = 0.02; and rs1544410; OR = 1.47 [CI 1.03–1.47], p = 0.02), which play a role in the etiology of GD through mechanisms other than reducing VitD levels, could well be involved (13). However, the latter proposed mechanisms are as yet working hypotheses derived from experimental work. Another point was the percentages of smokers in the two groups, this in the placebo group being almost double that of the VitD group; though the percentage was not significant, smoking could possibly have negatively affected muscle restoration by increasing ROS toxicity, as recently reported (6), it may slow down recovery in GD, reduce ATD efficacy, and contribute to resistance to GO treatment, thereby delaying remission of the disease.
The use of different VitD doses would have been helpful, enabling evaluation of dose–response or safe-limit dosages, which, however, is not possible in this type of trial. Clearly, more trials are necessary to determine whether supplemental VitD in GD patients with lower levels of 25(OH)D as well as lower doses of VitD could be beneficial. It was shown in a systematic review that VitD supplementation increases proximal muscle strength in adults with VitD deficiency but not in those with baseline 25(OH)D >25 nmol/L (14).
Impairment of muscle differentiation in response to VitD was also demonstrated in an in vitro study of injured human muscle cells, where muscle cell regeneration and differentiation were negatively affected in response to high-dose versus low-dose active VitD (calcitriol) or placebo (15). These findings point to a potential harmful effect of high-dose VitD through its direct interaction with skeletal muscle tissues. The pathways involved could be the following: the disturbed muscle regeneration or differentiation caused by the high-dose VitD supplementation led to diminished gain of muscle mass and muscle strength, which inevitably resulted in reduced QoL.
Low baseline VitD levels are frequently seen in patients with GD and GO. This raises the question of whether—and if so, to what degree—VitD status might be involved in the pathogenesis of GD, or whether it is a consequence of the immune-metabolic derangement. Clearly, there is a need to go back to the drawing board, to go beyond the cross-sectional trials that have been conducted, organizing instead randomized controlled studies that would examine low versus high doses of VitD supplementation in GD patients with both severe and mild forms of the disease. This would yield clearer results as to the effects of VitD on the various parameters in GD. For now, it seems advisable to routinely measure serum VitD concentrations in patients with GD, particularly in smokers and in those with increased titers of TRAb and/or with GO. If VitD deficiency is detected, low-dose VitD should be administered. While VitD is well known for its remarkable ability to modulate both innate and adaptive immune responses, VitD deficiency being associated with increased autoimmunity and susceptibility to infection, great care must be taken with the doses administered.