Laboratory Evaluation

Various studies have advocated for the routine screening of serologies associated with AI diseases including T3, T4, thyroid-stimulating hormone (TSH), thyroid autoantibodies, antinuclear antibodies (ANA), fasting blood glucose levels, complete blood count, vitamins B ₁₂ and D, and antiparietal cell antibodies. Ingordo and colleagues evaluated circulating antibodies in vitiligo patients and found that 41.8% of patients had at least 1 circulating antibody with the highest being anti–thyroid peroxidase antibody (25.6%) followed by anti-thyroglobulin (23.4%), ANA (16.8%), and gastric antiparietal cell antibodies (7.8%). Further laboratory screening recommendations are discussed with each appropriate disease.

Ocular and Auditory Abnormalities

Melanocytes exist not only in the skin, but also in mucous membranes, eyes (including the uveal tract and retinal pigment epithelium), inner ears, brain, leptomeninges, heart, hair bulbs, and adipocytes. Ocular and auditory abnormalities can also occur in association with vitiligo owing to the presence of melanocytes in these tissues.

Melanin plays several important roles in creating and maintaining the structure and function of the auditory system as well as affecting the transduction of the auditory stimuli in the inner ear. The heaviest pigmentation is located in the scala vestibuli of the membranous labyrinth of the inner ear, where melanocytes and melanin are responsible for normal function of the stria vascularis, development of the endolymphatic potentials, and preservation of the ion and fluid gradient between the endolymph and perilymph ( Fig. 1 ). Vitiligo patients can have profound auditory abnormalities or more subtle findings owing to alteration of melanocytes. Clinical studies show that 12% to 18% of vitiligo patients have sensorineural hearing loss. Gopal and colleagues found mild hearing loss (hypoacusis) to be present in up to 20% of vitiligo patients. Other studies have found hypoacusis to occur in 4% to 20% of vitiligo patients, although many of these patients may not have been aware of this loss. A Turkish study found that 37.7% of vitiligo patients had auditory abnormalities, including unilateral and bilateral hearing loss. An Egyptian study found that 60% of vitiligo patients had cochlear dysfunction compared with zero patients in their control group. They did not find the presence of the cochlear dysfunction was affected by vitiligo type (nonsegmental vitiligo vs segmental vitiligo).

( A ) Components of the cochlea ( B ) Components of the lateral wall within the cochlea. Melanocyes and melanin are located in the stria vascularis which, is in the scala vestibuli of the membranous labyrinth of the inner ear. They are responsible for normal function of the stria vascularis, development of the endolymphatic potentials, and preservation of the ion and fluid gradient between the endolymph and perilymph.

Vitiligo patients may also have ocular abnormalities that can affect the iris and retinal pigment epithelium, resulting in uveitis. One study found that 16% of vitiligo patients had ocular abnormalities compared with 5% of the control patients. These ocular abnormalities included uveitis as well as pigmentary changes of the retinal pigmented epithelium and iris. The association of vitiligo with ocular, auditory, and neurologic abnormalities provides further support for vitiligo being a systemic disease.

Abnormal auditory and ocular findings are also present in association with other AI conditions in unique syndromes, such as VKH, Alezzandrini syndrome, and APG. VKH is an uncommon multisystem, AI disease that affects organs containing melanin and can result in bilateral uveitis, hypoacusis, mengingoencephalitis, poliosis, vitiligo, and alopecia. The disease often begins with neurologic symptoms and then progresses to the ophthalmic phase, and finally the cutaneous manifestations. The etiology is still being investigated, but it is thought to be secondary to a CD4 ⁺ T-cell–mediated AI process against melanocytes. The condition is often thought to be triggered by an infectious agent in individuals who are susceptible genetically. Several susceptibility alleles have been linked with VKH, including HLA-DRB1*045, HLA-DR4, and HLA-DR53. Alezzandrini syndrome is another rare condition in which individuals develop unilateral retinal pigment epithelium degeneration and hearing loss with ipsilateral facial vitiligo and poliosis.

Vitiligo can be present in all types of APG, but is most commonly part of APG type 3, specifically type 3C. APG consists of AI diseases associated with multiple endocrine gland insufficiencies. APG 3C involves AITD plus skin, neural, or neuromuscular disease. The most accepted theory underlying the cause of APG relates to the AI genetic hypothesis involving genes associated with regulation of the immune system. APG has been associated with vitiligo in up to 21% of patients with APG type 1 having vitiligo. Amerio and colleagues found that, among 113 vitiligo patients, 31 had APG (most had the 3C subtype, AITD, and vitiligo), and suggested that in cases positive for antithyroid antibodies, other autoantibodies should be tested for including anti–gastric parietal cell, anti–pancreatic islet cell, and anti–adrenal gland. Vitiligo can also occur as part of AI polyendocrinpathy–candidiasis–ectodermal dystrophy syndrome caused by an AIRE gene mutation.

Alopecia Areata

AA has been reported in vitiligo patients with a frequency ranging from 1.2% to 16%. Vitiligo is also 4 times more common in patients with AA than in the general population. Studies in children with vitiligo have found an association with AA in 1.1% to 2.6%. Although there are antigenic differences between the distinct melanocyte populations that exist in the follicular epithelium and in the epidermis, the 2 conditions also share many similarities. Both conditions share similar pathogenic factors, including autoimmunity, genetic inheritability, and environmental triggers. From an immune standpoint, the conditions may be related through a shared underlying stimulation of a proinflammatory T helper-1 cell–mediated immunologic response or inactivation of a suppressor T-cell–mediated response. Finally, in a recently published study, Gan and colleagues hypothesized that a common antigen may exist between AA and certain forms of vitiligo, namely follicular vitiligo.

Atopic Dermatitis

Some studies have found AD to occur in higher than expected frequencies in association with vitiligo ( Fig. 2 ). A metaanalysis study found higher odds of AD in patients with vitiligo than control patients. Furthermore, early onset vitiligo (<12 years) was associated with significantly greater odds of AD compared with those with late-onset vitiligo, even when correcting for potential confounders such as age, gender, vitiligo severity, and disease duration. In a Korean population-based study, Lee and colleagues found that 5.53% of the vitiligo patients also had AD. Another study found that atopic disease was associated with vitiligo involving a body surface area of at least 76% as well itching or burning of the skin. The authors suggest that a history of atopic disease can be helpful to predict which vitiligo patients will experience progression to extensive disease. The proinflammatory state of AD is thought to be a potential predisposing factor for vitiligo. The association between the 2 conditions may also occur from common pathways activated in both disorders, including thymic stromal lymphopoetin and T helper-17 cells. Pruritus from AD can also lead to scratching and subsequent koebnerization of vitiligo. The 2 conditions may also share a common genetic mutation; however, the question of whether atopy predisposes one toward vitiligo or if the 2 conditions coexist remains to be answered.

A 3-year-old boy with vitiligo and atopic dermatitis on his dorsal hands.

Celiac Disease

Celiac disease is an immune-mediated enteropathy with a US and European prevalence of about 1%. Several cases in the literature have reported vitiligo patients with celiac disease, some of whom had an improvement in their vitiligo after consuming a gluten-free diet. Celiac disease autoantibodies have been found to be more common in some vitiligo patients, suggesting a possible common genetic basis and pathophysiologic pathway for both diseases. Dermatitis herpetiformis, an immunobullous skin disorder also related to gluten sensitivity, has occurred reportedly with vitiligo in several cases. It has been speculated that vitiligo may occur as a koebnerization reaction secondary to the inflammation triggered by dermatitis herpetiformis or the 2 conditions may be correlated pathologically through circulating immune complexes. Further studies are needed to shed light on the strength of the association between vitiligo and these gluten-sensitive disorders, as well as the role that gluten-free diets might play in improving vitiligo in these patients.

Diabetes Mellitus

Type 1 diabetes mellitus and vitiligo are both AI diseases, but there may also be an additional shared inflammatory link between the 2 conditions. A recent study found that vitiligo patients with type 1 diabetes mellitus had higher levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β compared with patients with only vitiligo, type 1 diabetes mellitus, or controls. In particular, IL-6 serum levels were significantly higher in patients with both conditions, suggesting that IL-6 may play an important role in the pathogenesis of patients who share both conditions and could be a potential therapeutic target for these patients. The relationship between vitiligo and type 2 diabetes mellitus has also been investigated in several studies as possibly coexisting with vitiligo or having a causal relationship with it. Several small studies have found that nearly 3% to 5% of individuals with type 2 diabetes mellitus have vitiligo. Various pathogenic mechanisms are thought to be involved in this association including oxidative stress, free radicals, and growth factors that have a cytotoxic effect on melanocytes. Larger studies are needed to further elucidate this potential association.

Pernicious Anemia

Several reports have found an increased association between vitiligo and PA. The incidence of vitiligo in PA has been found to be 4 to 10 times higher than the general population and more common with late-onset vitiligo. Other studies have failed to find an increased association between the 2 conditions and have not advocated for routine screening of folic acid, vitamin B ₁₂ , or anti–gastric parietal cells.

Helicobacter pylori Infection

Various microbial agents through their communication with the environment and the immune system have been suggested to play a role in the pathogenesis of vitiligo including hepatitis C, cytomegalovirus, and human immunodeficiency virus (HIV). These agents are thought to cause AI disease through antibody production, molecular mimicry, high cytokine levels, major histocompatibility complex activation, regulatory T-cell dysfunction, immune complex formation, and chronic inflammatory damage. More recently, studies have evaluated whether H pylori may also be a trigger for vitiligo. H pylori affects 50% to 80% the world’s population and has been linked with various AI and systemic diseases. In addition to causing gastric inflammation, including gastric ulceration and carcinogenesis, H pylori leads to systemic inflammation through production of tumor necrosis factor-α, IL-6, IL-8, and IL-1β. These systemic effects may lead to a change in the cutaneous microenvironment that subsequently causes melanocyte damage. A recent study found the prevalence of H pylori to be 64.7% in vitiligo patients compared with 33.3% in the control group. Another study supporting this association advocates for H pylori eradication in vitiligo patients with dyspepsia. Further studies are needed to better understand the association between H pylori and vitiligo, including whether H pylori serves as a trigger for vitiligo and if its eradication affects the disease course of vitiligo.

Human Immunodeficiency Virus Infection and AIDS

A limited number of case reports have found individuals with HIV and AIDS who develop vitiligo; however, studies have not shown whether individuals with HIV have vitiligo at a higher frequency than the general population. HIV-associated vitiligo was first reported in 1987, with the majority of cases resulting in vitiligo onset after the diagnosis of HIV or AIDS. Several mechanisms have been proposed to account for this pathogenesis including immune disequilibrium among cytotoxic, suppressor, and helper T cells, direct HIV activation of melanocytes, and cellular cytotoxicity against melanocytes. Because AI disease occurs when there is a loss of tolerance to autoantigens, HIV may be the stimulus for loss of peripheral tolerance to self-reactive B and T cells. One case report found a 5-fold increase in CD8 ⁺ cells in a patient who developed vitiligo after having HIV. This significant increase in CD8 ⁺ count may also affect T-cell cytotoxicity in the pathogenesis of vitiligo.

Lichen Sclerosus et Atrophicus and Morphea

Lichen sclerosus et atrophicus and morphea have also been associated with vitiligo; however, this association has been mainly in case reports rather than large epidemiologic studies. Lichen sclerosus et atrophicus is considered by some to be an AI disease based on the presence of antibodies to extracellular matrix protein 1 and its association with other AI diseases. Morphea has also been linked to neurologic, infectious, and immunologic abnormalities, as well as other AI diseases. A recent cross-sectional study done in the United States in 1873 patients found a higher prevalence of linear morphea (0.2%) compared with the general US population (182 cases per 100,000). The presence of lichen sclerosus et atrophicus and morphea in several vitiligo patients has raised speculation about a shared AI basis among these conditions as well as a possible shared decrease in T-regulatory cells, leading to a loss of tolerance.

Psoriasis

Psoriasis, which has significant immune system alterations, has also been associated with vitiligo. This concomitance could be owing to chance, given that in several epidemiologic studies, the percentage of vitiligo patients with psoriasis has ranged from 1% to 2.2%, which corresponds with the 1.5% to 2% frequency of vitiligo in the general population. Sheth and colleagues, however, found that the prevalence of psoriasis in their study of vitiligo patients to be higher at 7.3% with psoriasis and hypothyroidism being the most commonly associated AI diseases in Caucasian and Hispanic vitiligo patients. In the majority of case reports (63%), vitiligo occurred first, followed by the development of psoriasis. A common AI origin of the 2 conditions could be IL-17A produced by T-helper 17 cells, which has been implicated in the pathogenesis of psoriasis and has been speculated as having a role in the pathogenesis of vitiligo. Another study found that the strongest predictors of concomitant psoriasis and vitiligo were having inflammatory-type vitiligo and a positive family history of cardiovascular disease. In addition to shared inflammatory pathways and genetic susceptibility, a locus in the MHC region has been identified that is associated with both psoriasis and vitiligo. Similar to AD, the Koebner phenomenon may be another reason to account for the concomitance and colocalization of the 2 conditions.

Rheumatologic Diseases

Rheumatologic diseases including RA, SLE, spondyloarthritis, and SS have also been associated with vitiligo. Sheth and colleagues found that 2.2% of vitiligo patients had SLE and 2.9% had RA. Interestingly, rates of RA and SLE were more common among African Americans than other races. In the same population, 41% of the patients had elevated anti-ANA titers and 66.7% had positive rheumatoid factor. Gill and colleagues found a frequency of 0.2% having SS and 0.3% having SLE with the latter also only occurring in black patients with vitiligo. Chen and colleagues conducted a nationwide population-based study in Taiwan and in their age- and gender-stratified analysis, the risk of SLE and SS was higher in vitiligo subjects ages 60 to 79 years, whereas RA was higher in only females of the same age group. Tumor necrosis factor-α polymorphisms have been associated with susceptibility to both RA and vitiligo. Spondyloarthritis, which includes ankylosing spondylitis, Reiter syndrome, and reactive and psoriatic arthritis, as well as arthritis associated with inflammatory bowel disease, was found in another study to affect 3.4% of vitiligo patients. These studies show that rheumatologic disease in vitiligo patients may be affected by demographic factors such as age, gender, and race.

The prevalence of positive ANA in vitiligo patients has also varied with percentages ranging from 2.5% to 41%. Many patients with a positive ANA may have low titers without concomitant SLE or rheumatologic disease. One study found positive ANA levels in 19.57% of the vitiligo patients with no individuals or their family members having SLE. Some studies have cited the presence of circulating antibodies as being associated with a longer duration of vitiligo and an older age of onset of the disease. Other studies that failed to find a higher association of positive ANA titers in vitiligo patients have argued that it should not be screened routinely.

Thyroid Disease

Many vitiligo patients are often found to have thyroid abnormalities resulting in subclinical or clinical thyroid disease. The prevalence of thyroid disease is 3 to 8 times higher in vitiligo patients, with AITD being the AI disorder most commonly associated with vitiligo. Hypothyroidism tends to be the most common of the associated thyroid disease followed by Graves disease. Vitiligo often precedes thyroid disease with the risk of developing thyroid disease increasing with age and doubling every 5 years. This increased association with thyroid disease has supported the AI basis of vitiligo and suggested that the 2 diseases may share a common AI etiology. This includes a shared existence of T-helper 1 cell–driven AI processes. Other studies have also suggested that oxidative stress and autoimmunity interact and work together in thyroid and vitiligo autoimmunity pathways causing one condition to lead to the other. Studies from across the world have found varying percentages of vitiligo patients with concomitant thyroid disease ranging from 1.3% to 40%. An Iranian study found the prevalence of AITD to be 21.1%, and found that those with a positive family history of AI diseases had a decreased response to vitiligo treatment. A Belgian study found that patients with vitiligo and thyroid disease, which was 15.4% of their patient population, had a higher affected body surface area as well as a predilection to depigmentation of the joints and acral skin. A Canadian study by Sawicki and colleagues found hypothyroidism in 19.0% of vitiligo patients with twice as many females being affected compared with males. In Turkey, 55% of vitiligo patients have been found to have thyroid disease, and in Brazil, the rate was 22%; Indian studies have shown a range of 3% to 11%.

This reality has led many to advocate for the routine screening of thyroid function tests to discover the development of thyroid disease at an early stage. A Chinese study examined serologies in vitiligo patients and found that elevated free T3 and TSH were the laboratories that differed the most from the control group. Many vitiligo patients (2.2% to 50%) have also been found to have positive antithyroid antibodies against thyroglobulin, thyroid peroxidase, and TSH receptor. In some patients, the presence of positive thyroid antibodies can exist without the presence of thyroid dysfunction. Thyroglobulin antibodies and in particular TPO-antibodies may be helpful in serving as an immune screening marker in vitiligo patients who have subclinical AITD or those who may have not yet developed thyroid disease but are at risk for it. The risk of these antibodies being increased in vitiligo patients is 5 times higher than the general population, and may be present up to 7 years before development of thyroid disease.

Screening guidelines for thyroid serologies vary, with some researchers recommending routine screening every 1 to 3 years in all vitiligo patients, whereas others recommend it for those who are symptomatic or have higher risk factors for it. Recommendations of which thyroid tests to perform also vary, with some studies advocating solely for TSH and others supporting additional testing of thyroid antibodies to pick up risk of future development of AITD. One study found that those at higher risk for developing AITD includes female patients, patients with longer duration of disease, and greater body surface area. In another study, the risk of AITD with vitiligo was found to be associated independently with disease duration and the risk of patients with vitiligo developing AITD was found to double every 5 years. These results were corroborated by another study, which recommended screening of women every 2 years owing to an association between AITD and females with long duration of disease. Pediatric studies have also recommended screening in children owing to thyroid hormones playing an important role in normal childhood development. Other studies have advocated for it to be tested in those who have a family history of thyroid disease, those with long disease duration, or those with stressful life events. It is this author’s opinion that vitiligo patients should be screened for thyroid disease with TSH and thyroid antibody testing at least every 1 to 2 years. For providers who prefer to not order initial laboratory evaluation, at a minimum patients should be questioned annually about thyroid symptoms with a thorough review of systems. Laboratory testing can then be reserved for those with any positive symptoms.