Titanium Dioxide in Toothpaste Causing Yellow Nail Syndrome

Discussion

YNS is an uncommon disorder. More than 300 cases have been reported in literature. In 1964, Samman¹ described 13 patients, all of whom had thickened and slow-growing yellow nails, and 10 of whom also had lymphedema. This was the first reported case series of YNS. In 1966, Emerson⁴ added pleural effusion as a frequent feature of YNS. In 1979, Runyon et al⁵ described the classic triad of YNS: yellow nails, lymphedema, and pleural effusion. Later, bronchochiectasis, rhinosinusitis, recurrent pneumonia, and chronic cough were also recognized as frequent manifestations of YNS.⁶ Current opinion supports the replacement of pleural effusion with respiratory manifestations as the third criterion. The clinical features of YNS are variable among individuals and can vary over time. Only 27% of YNS patients have all 3 classic symptoms simultaneously.^7,8 Hiller et al⁶ suggested the diagnosis of YNS can be made when a patient presents with 2 of the 3 classic symptoms at any given time without another explanation.

In a previous study, 89% of patients with YNS had yellow nail discoloration.⁹ Typical abnormalities of the nails included yellow discoloration, thickening, slow growth, transverse ridging, excessive curvature, and onycholysis.¹⁰ YNS usually affects all 20 nails. Improvement of nail symptoms is often associated with treatment of the respiratory syndrome.¹¹ Lymphedema usually involves the lower limbs symmetrically, but it can also affect the upper limbs, face, and eyelids.¹² About 40% of patients with YNS present with pleural effusion. Most of the pleural effusions are bilateral (68.3%), consisting of exudates with lymphocytic predominance.¹³

The pathogenesis of YNS remains unknown. Some familial cases have been described¹⁴; however, most cases are sporadic or acquired. The hypothesized mechanisms of YNS include anatomic or functional lymphatic abnormalities and microvasculopathy with protein leakage.^9,15,16 However, these mechanisms cannot explain the nail abnormality, because patients who have lymphedema of any other etiology do not present with yellow nail discoloration.

Recently, a relationship between titanium and the development of YNS was reported. In 2011, Berglund and Carlmark³ reported that all of their patients with YNS had a history of titanium exposure. In their 34 patients, 26 had received titanium implants; the other 8 patients were exposed to high amounts of titanium dioxide either in drug tablets or in confectionaries. Nail clippings of these patients were analyzed by energy dispersive radiograph fluorescence, and titanium was detected in all samples (range: 1.1–170 μg/g−1). Titanium was not found in the nails of healthy people, even those exposed to titanium.

Titanium is a lustrous metal with a silver color, low density, and high strength. In medical uses, titanium can be alloyed with aluminum or iron, among other elements, to produce strong, lightweight alloys for orthopedic or dental implants. Berglund and Carlmark³ hypothesized that titanium ions are released from titanium implants by galvanic actions with dental gold or amalgam implants or by the oxidative action of fluorine. Removal of gold could alleviate the symptoms of YNS. After Berglund and Carlmark’s study,³ there have been 3 subsequent reports that support their findings.^17–19 All of the reported patients had a history of titanium exposure preceding the development of YNS. The titanium levels from the patients’ fingernails were all elevated. Withdrawal of titanium exposure led to improvement of the symptoms in the early stage of the disease,¹⁸ but did not help in a patient with advanced disease.¹⁹

Another source of titanium exposure is by uptake of titanium dioxide from the digestive tract. The brightness and high refractive index of titanium dioxide have made it widely used as a color additive or coating agent in sunscreen, toothpaste, medication tablets, chewing gum, confectionaries, and cosmetics. YNS that is associated with taking medical tablets containing titanium dioxide has been repeatedly reported, and symptoms are at least partially reversible after discontinuing these drug tablets.^3,20 For our patient, a thorough history of titanium exposure suggested that swallowing of toothpaste was the potential cause of her YNS. With meticulous avoidance of swallowing toothpaste, she had amelioration of her yellow nail discoloration and her respiratory symptoms also improved over time. Furthermore, no titanium was detected in the nails 3 years later.

The hypothesis that YNS is related to titanium exposure may explain some characteristics of this syndrome. Most patients with YNS are middle-aged adults or elderly adults, and these groups of patients have a greater prevalence of implants. YNS has been reported to be associated with other systemic diseases, such as malignancy,^21,22 thyroid disease,⁹ nephrotic syndrome,²³ rheumatoid arthritis,²⁰ obstructive sleep disorder,²⁴ and tuberculosis.²⁵ The possible explanation is that patients with systemic diseases are more likely to be taking medicines that contain titanium dioxide.²⁰

By contrast, YNS is rarely reported in children. In reviewing the 19 pediatric cases of YNS reported in the literature (Table 1), we found that 6 of them had a history of family tendency. Yellow nails and recurrent respiratory infections were the most common presentations. Lymphedema was present in 12 cases. Pleural effusion was present in 5 cases (4 at birth and 1 later). Bronchiectasis was diagnosed only in 4 cases. We find that there are 2 age peaks in the incidence of YNS. Most pediatric cases of YNS presented at birth, and 2 affected infants were born to mothers who had YNS.^26,27 Fetal hydrops may be the clinical presentation of lymphedema in newborns. We speculate that titanium may cross through the placenta from mother to baby. Another peak of incidence of YNS is between 6 and 10 years of age, which may be explained by the fact that children at this age have had exposure to candy or children’s toothpastes that contain titanium dioxide.

Titanium is a widely used material, but YNS is a relatively rare syndrome. Only rarely do people exposed to titanium ever develop YNS. The duration and amount of titanium exposure, sensitization to titanium or titanium dioxide, susceptibility to galvanic erosion, and other coexisting factors may be responsible for development of YNS. It is likely that specific patients may have an underlying genetic or immunologic susceptibility to develop YNS when exposed to titanium or titanium dioxide. Additional research is warranted to determine the relationship between YNS and titanium exposure.

Our patient presented with sinusitis and chronic cough, which are common findings in children. Without noting the nail changes, YNS can be easily overlooked and underdiagnosed by a physician. Therefore, we suggest that the diagnosis of YNS should be considered in children with chronic respiratory manifestations. If nail changes are found, energy dispersive radiograph fluorescence is an appropriate tool to analyze the titanium level in nail clippings.³⁹ Currently, there is no specific treatment for YNS; treatment decisions are always based on clinical judgment, and the responses are variable. Based on the hypothesis that YNS may result from titanium, physicians should trace the possible source of titanium dioxide exposure for their patients. Avoiding exposure to titanium dioxide may benefit children with this rare syndrome.