Nail Amino Acid and Trace Element Profiles and Their Association with Clinical Severity in Nail Psoriasis

Introduction

Psoriasis is a chronic, immune-mediated inflammatory disease that affects approximately 2–3% of the global population.¹ It frequently extends to skin appendages, particularly the nails, leading to significant functional impairment and psychosocial distress. Nail involvement is observed in 50–79% of patients with cutaneous psoriasis and up to 80% of those with psoriatic arthritis.² Common nail changes including pitting, subungual hyperkeratosis, onycholysis, and discoloration not only reflect disease severity but may also serve as early indicators of psoriatic arthritis.^3,4

The Nail Psoriasis Severity Index (NAPSI) is widely used in research to quantify nail involvement.⁵ Yet, it does not directly reflect the underlying biological changes in the nail. Non-invasive biochemical markers may serve as a useful complement by indicating disease activity at a molecular level and helping relate these changes to clinical severity.^6,7

The nail unit is a biologically active structure composed of keratinized tissues, requiring a coordinated supply of amino acids and trace elements for proper growth and differentiation. These biochemical components serve as structural and enzymatic cofactors essential for keratin production and nail integrity.^8,9 Despite this, there is a significant lack of studies investigating the biochemical composition of nails in patients with psoriasis, particularly regarding essential amino acids and trace elements.

The rationale of this study originated from the attempt to understand the biochemical background underlying the altered nail morphology observed in psoriasis. Just as the distinction between a diamond and a rock lies not only in their appearance but in their chemical composition, the difference between dystrophic and non-dystrophic nails in psoriasis may also stem from biochemical, rather than purely structural, alterations. This concept is supported by prior literature on nail biology⁸ and biochemical alterations in inflammatory skin diseases.¹⁰ Therefore, instead of including healthy individuals as controls, we selected psoriasis patients without nail involvement. A similar disease-internal comparison strategy has been applied in previous studies, in which psoriasis patients were evaluated according to the presence or absence of nail involvement rather than compared with healthy controls.¹¹ This design allowed us to identify nail-specific biochemical differences associated with morphological changes, independent of the systemic effects of psoriasis itself. A comparison with healthy subjects could have highlighted psoriasis-related but nail-nonspecific alterations, potentially masking these subtle distinctions. The study does not aim to define a mechanistic pathway, but rather to characterize how the biochemistry of the affected nail differs from that of the unaffected nail within the same disease spectrum.

The nail plate is primarily composed of hard keratin, whose structural integrity depends on keratin-associated proteins, disulfide bonding, and a balanced composition of specific amino acids and trace elements.^2,12 Alterations in these biochemical components may influence nail rigidity, cohesion, and growth.⁸ Based on their known structural or metabolic relevance to nail biology, selected trace elements and amino acids have been investigated to better understand their potential association with nail pathology in psoriasis. This approach may help determine whether biochemical changes within the nail plate are associated with nail involvement and clinical severity.

Therefore, this study aimed to evaluate the levels of selected trace elements and amino acids in nail samples of patients with psoriasis, comparing those with and without nail involvement. Furthermore, we explored the correlation between the severity of nail involvement and biochemical alterations to identify potential biomarkers that may reflect disease activity and assist in clinical monitoring.

Materials and Methods

Study Design and Participants

This study was designed as an exploratory, hypothesis-generating investigation aimed at characterizing nail-specific biochemical profiles in psoriasis.

This case-control study was conducted at the Department of Dermatology, Istanbul Medeniyet University Prof. Dr. Suleyman Yalçın City Hospital between October and December 2023. The study included adult patients clinically diagnosed with psoriasis who were not receiving any systemic treatment.

Participants were categorized into two groups based on the presence of clinical nail involvement. The Nail psoriasis group consisted of 30 patients diagnosed with psoriasis who exhibited clinically evident nail changes. In contrast, the control group included 27 psoriasis patients who showed no signs of nail involvement upon clinical examination. Nail samples were not obtained from unaffected nails of patients with nail psoriasis.

Inclusion criteria were: psoriasis duration ≥1 year, age ≥18 years, and nail involvement duration ≥6 months. Exclusion criteria included use of systemic medications, vitamin supplementation, comorbid chronic diseases (eg, diabetes, cardiovascular disease, cancer), positive KOH findings, or exposure to nail cosmetics or chemicals within one week prior to sample collection. Topical treatments for nail psoriasis were not included as an exclusion criterion, as such therapies are widely accessible and frequently used intermittently in routine clinical practice. Given that the study was conducted in a tertiary referral center, excluding patients with prior topical treatment would have substantially limited the representativeness of the study population.

All participants provided informed consent. Demographic data including age, sex, smoking and alcohol use, presence of joint pain, disease duration, and Nail Psoriasis Severity Index (NAPSI) scores were recorded.

Ethical approval was obtained from the institutional review board (approval number: 2023/0633), and written informed consent was acquired from all participants. The study was funded by the Turkish Dermatology Association.

Sample Collection

Sterile nail clippings were collected from all participants. Care was taken to avoid contamination with external material. The samples were stored at +4°C in sterile containers. Nail clippings were obtained from a single fingernail of each participant. In the nail psoriasis group, the sampled nail was selected based on clinical involvement, with priority given to the thumbnail if affected. If the thumbnail was unaffected, another clinically involved fingernail was chosen. In the control group, nail clippings were collected from the thumbnail. Toenails were not included in the study. Each nail clipping was carefully divided into two equal portions to allow for separate analyses of trace elements and amino acids.

Biochemical Analysis

Nail samples were subjected to trace element and amino acid profiling.

Trace Elements Analysis

Nail concentrations of chromium (Cr), copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), magnesium (Mg), and selenium (Se) were measured using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). Nail samples were digested with concentrated nitric acid followed by perchloric acid under controlled heating. After cooling and dilution with ultrapure water, the samples were filtered and analyzed in duplicate. Element-specific calibration curves and reagent blanks were used to ensure accuracy. Final values were expressed as micrograms per gram (µg/g) of dry tissue.

Amino Acids Analysis

Twenty amino acids (Phenylalanine, Leucine, Serine, Tyrosine, Cysteine, Tryptophan, Proline, Histidine, Glutamine, Arginine, Isoleucine, Methionine, Threonine, Asparagine, Lysine, Valine, Alanine, Aspartic acid, Glutamic acid, and Glycine) were quantified using Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS). Nail samples were rinsed with deionized water and cleaned with a mixture of chloroform, methanol, and acetone. After drying, the nail samples were transferred into glass tubes with screw caps. Subsequently, 200 µL of 6M hydrochloric acid (HCl) and 200 µL of a reagent containing amino acid standards (R1) were added to each sample at a 1:1 ratio. The samples were hydrolyzed by incubation at 110°C for 24 hours to release amino acids through protein degradation.

After cooling to room temperature, the hydrolyzed samples were filtered through a 0.22 µm PVDF membrane filter and transferred into microcentrifuge tubes. The filtered samples were then placed in a vacuum concentrator at 45°C for approximately 4 hours until complete evaporation of the liquid phase. The resulting dry residues were reconstituted in 400 µL of a solution containing 20% methanol and 0.1% formic acid, followed by filtration through a 0.22 µm PVDF membrane filter before analysis. Results were normalized to dry tissue mass and reported in nanomoles per milligram (nmol/mg). All samples were analyzed in duplicate.

Statistical Analysis

Data was analyzed using SPSS software version 25.0. Normality of distribution was assessed with the Shapiro–Wilk test. Student’s t-test or Mann–Whitney U-test was used to compare continuous variables between groups. Spearman correlation analysis was used to assess relationships between NAPSI scores and biochemical parameters. A p-value of <0.05 was considered statistically significant.

In addition, post-hoc power analyses were conducted based on the observed effect sizes for the two-group comparisons (two-tailed, α=0.05). Medium-to-large effect sizes were observed for iron, chromium, manganese, selenium, zinc, as well as proline, histidine, glycine, asparagine, and threonine, with achieved power ranging between 70–95% in the current sample. In contrast, variables with small effect sizes yielded limited statistical power, and ≥80–100 participants per group would be required to reach 80% power. For correlations with NAPSI scores (r=0.32–0.44), the achieved power was 40–60%, indicating that a total sample size of approximately 50–85 patients would be necessary to achieve 80% power.

The exploratory nature and limited sample size of this pilot study should be acknowledged. Due to the lack of previous data on nail-based biochemical alterations in psoriasis, an a priori power calculation was not feasible. As a result, certain analyses did not reach 80% statistical power, indicating that larger multicenter studies will be required to confirm our preliminary findings and establish more definitive effect estimates.

Results

Demographic Characteristics

A total of 57 patients were included in the study. Of these, 30 patients had clinical nail involvement (nail psoriasis group) and 27 had no nail involvement (control group). There were no statistically significant differences between the two groups in terms of age, sex, smoking, alcohol use. However, disease duration was significantly longer in patients with nail involvement compared to those without (13.3 ± 10.9 vs 8.7 ± 8.6 years, p = 0.048) (Table 1). In the Nail Psoriasis Group, the mean NAPSI score was 44.1 ± 20.6 (median: 49, range: 12–80), indicating a wide spectrum of nail involvement severity among patients. Inclusion of this metric provides further insight into the clinical heterogeneity of the group and enables biochemical correlations to be interpreted in light of clinical severity.

Table 1 Demographic and Clinical Characteristics of Study Groups

Trace Element Levels in Nail Samples

The mean levels of several trace elements in nail samples differed significantly between the two groups (Table 2):

Table 2 Nail Trace Element Levels in Psoriasis Patients (Mean ± SD)

Chromium (Cr): Significantly lower in the nail psoriasis group (p = 0.001)

Copper (Cu): Significantly lower in the nail psoriasis group (p < 0.014)

Iron (Fe): Significantly lower in the nail psoriasis group (p = 0.001)

Manganese (Mn): Both Mn2576 and Mn2605 isotopes were significantly lower (p = 0.001 each)

Selenium (Se): Decreased in the nail psoriasis group (p = 0.003)

Zinc (Zn): Significantly reduced (p = 0.010)

No significant difference was observed for Magnesium (Mg) (p = 0.330).

Amino Acid Levels in Nail Samples

Among the 20 amino acids analyzed, several showed significant differences (Table 3):

Table 3 Nail Amino Acid Levels in Psoriasis Patients (Mean ± SD)

Asparagine (p = 0.004), Glycine (p = 0.004), Proline (p = 0.001), and Threonine (p = 0.007) levels were significantly lower in the nail psoriasis group.

Histidine was found to be significantly higher in patients with nail involvement (p = 0.002)

Correlation with Nail Psoriasis Severity (NAPSI)

Correlation analysis revealed that decreased levels of specific trace elements and amino acids (eg, Zinc, Selenium, Glycine, Proline) were negatively correlated with NAPSI scores, indicating that more severe nail involvement was associated with lower levels of these biochemical markers. A positive correlation was observed between histidine levels and NAPSI scores (r = 0.42, p = 0.002) (Table 4).

Table 4 Correlation of Nail Trace Elements and Amino Acids with NAPSI Score

Multivariate Logistic Regression

Multivariate logistic regression identified nail selenium (OR = 0.585, p = 0.011), nail histidine (OR = 1.033, p = 0.019), and nail asparagine (OR = 0.959, p = 0.016) as independent predictors of nail involvement.

Subgroup Analysis by Disease Duration

Patients with longer disease duration (≥10 years) showed greater reductions in nail trace element and amino acid levels compared to those with a disease duration <10 years, particularly for Selenium and Proline.

Discussion

This study investigated the biochemical composition of nails in patients with psoriasis, focusing specifically on trace element and amino acid profiles. We demonstrated that patients with nail psoriasis had significantly lower levels of chromium, copper, manganese, selenium, and zinc compared to psoriasis patients without nail involvement. Similarly, several amino acids particularly asparagine, glycine, proline, and threonine were also reduced. Notably, histidine levels were increased in the nail psoriasis group. Our findings demonstrate an association between nail involvement in psoriasis and altered biochemical profiles within the nail unit. However, the directionality and underlying mechanisms of this association remain to be clarified.

In our study, disease duration was significantly longer in patients with nail involvement compared to those without (13.3 ± 10.9 years vs 8.7 ± 8.6 years, p = 0.048). This finding suggests that nail changes may develop progressively in the context of chronic inflammation. The observed association between prolonged disease duration and biochemical alterations in the nail matrix may reflect cumulative effects of chronic inflammation. However, whether these metabolic changes contribute to or merely result from nail pathology remains uncertain. Alternatively, nail involvement might reflect a more persistent, treatment-resistant, or extensive form of psoriasis.

Trace elements are essential cofactors in numerous enzymatic and cellular processes, including keratinocyte differentiation, oxidative stress regulation, and epithelial barrier maintenance. The reduction in selenium and zinc observed in our study aligns with previous findings suggesting their role in antioxidant defense and keratin metabolism.^13–15 Selenium, in particular, is incorporated into selenoproteins such as glutathione peroxidase, which may modulate inflammatory processes in psoriatic tissue.^15,16 Selenium, asparagine, and histidine were identified as independent variables statistically associated with nail involvement in psoriasis. These findings suggest that biochemical markers in nail tissue may hold potential for further exploration as non-invasive indicators.

Zinc is also critical for matrix metalloproteinase activity and tissue remodeling. Zinc is essential for keratinocyte proliferation and DNA synthesis and has known anti-inflammatory effects.^15,17,18 Reduced nail zinc levels in this study align with earlier findings of low serum zinc in psoriasis and suggest potential depletion at the site of keratin production.^19–21 The discrepancy between serum and nail copper levels is noteworthy: while previous reports describe elevated serum copper in psoriasis,¹⁹ our study found significantly decreased nail copper. This may reflect differential compartmentalization or altered incorporation of copper into keratinized tissue under inflammatory stress.

The amino acids found to be decreased in the nail psoriasis group—glycine, proline, threonine, and asparagine—are integral to collagen synthesis and keratin structure.²² Their deficiency may impair the integrity and function of the nail matrix and nail bed, potentially contributing to dystrophic changes observed clinically.^10,23,24 Glycine and proline are not major structural components of keratin; however, their role in collagen synthesis and extracellular matrix organization may still be relevant to nail unit biology. However, these observations should be interpreted as biologically plausible associations rather than direct explanations for the classical structural changes seen in psoriatic nail dystrophy.

Histidine plays a multifaceted role in cutaneous homeostasis and immunity. As a histamine precursor, it contributes to inflammation by promoting vasodilation, pruritus, and leukocyte recruitment. It also provides antioxidant defense by scavenging reactive oxygen species and supporting epidermal barrier integrity through its role in natural moisturizing factor and urocanic acid production.²² In our study, the elevation of histidine levels in psoriatic nails may represent a compensatory metabolic response aimed at counteracting oxidative stress and maintaining local barrier integrity in the inflamed nail unit.

Glutamine levels showed marked variability in the nail psoriasis group (1530.4 ± 3441.9 nmol/mg), with a standard deviation exceeding the mean. This may reflect outliers or high interindividual variability, potentially affecting statistical significance. Future studies should consider robust analyses or data verification to address this skewness.

A significant negative correlation between NAPSI scores and the levels of specific trace elements and amino acids suggests that as the severity of nail involvement increases, the metabolic disturbances become more pronounced. These observations raise the possibility that these biochemical markers may reflect nail disease burden in psoriasis.

In a serum-based LC–MS metabolomic study of psoriasis, significant reductions in glycine, proline, and asparagine levels were demonstrated, with these alterations correlating with inflammatory disease activity.²⁵ Similarly, in a plasma metabolomic profiling study of psoriasis, markedly reduced levels of asparagine, threonine, and glycine were reported, while histidine levels were preserved or increased in certain patient subgroups.²⁶ In a metabolomic comparison of lesional and non-lesional psoriatic skin, disruptions in amino acid metabolism were shown to be closely associated with keratinocyte hyperproliferation and tissue remodeling.²⁷ Furthermore, targeted serum amino acid profiling in generalized pustular psoriasis identified a characteristic “amino acid starvation” signature, marked by reduced levels of glycine, proline, asparagine, and threonine.²⁸ Finally, systematic evaluations of toenail clippings as biomarkers demonstrated that nail measurements of trace elements such as zinc, copper, manganese, and selenium reliably reflect long-term biological status.²⁹

To our knowledge, this is one of the few studies to focus specifically on the biochemical composition of psoriatic nails. There is growing evidence supporting the use of nail tissue, particularly toenails, as a biomarker for evaluating biochemical alterations in both localized and systemic conditions. For instance, Kilinc et al reported significantly lower levels of zinc, magnesium, and manganese in the toenails of patients with onychomycosis compared to healthy controls, while no significant differences were observed in onychocryptosis, a non-inflammatory nail disorder.³⁰ Similarly, Matthews et al demonstrated associations between toenail trace element levels and the risk of skin cancer, further supporting the relevance of nail tissue in biomarker studies.³¹ Moreover, large-scale reviews emphasize the value of nail trace element analysis for assessing long-term exposure and metabolic status.³² Collectively, these findings highlight the broader applicability of nail biochemical analyses; however, direct comparisons of nail biochemical profiles across different dermatological diseases remain limited and warrant further investigation.

Limitations of this study include its cross-sectional design and relatively small sample size. Additionally, while we excluded systemic treatment, other confounding variables such as diet, comorbidities, or supplement use may have influenced biochemical levels. Given the cross-sectional nature of this study, it is not possible to determine whether the observed biochemical alterations are a cause or consequence of nail involvement. Post-hoc power analyses further indicated that while medium-to-large effects were adequately powered, smaller effects and correlations remained underpowered, requiring larger cohorts for confirmation. The inclusion of patients with clinically evident nail psoriasis may limit the generalizability of the findings across the full spectrum of nail involvement, and this should be considered when interpreting the results. Future longitudinal studies with larger cohorts and functional assays are warranted to validate these findings and explore causality.

Furthermore, while nail biochemical analysis may provide additional insights into localized metabolic changes in psoriasis, its clinical utility remains uncertain. As this method relies on distal nail clippings, it may not accurately reflect current disease activity or allow early detection of treatment effects.

Conclusion

This study demonstrates that nail involvement in psoriasis is associated with significant alterations in the levels of specific trace elements and amino acids within the nail plate. Patients with nail psoriasis exhibited reduced levels of chromium, copper, manganese, selenium, zinc, as well as key amino acids such as asparagine, glycine, proline, and threonine. These biochemical changes were correlated with the severity of nail involvement, as assessed by NAPSI scores.

Our findings indicate that biochemical analysis of nail tissue may provide additional information about localized metabolic changes in psoriasis. In particular, selenium, asparagine, and histidine levels were significantly associated with nail involvement. These parameters may have potential as non-invasive biomarkers, but this requires confirmation in future prospective studies.

Further longitudinal and mechanistic studies are warranted to confirm these associations and to better understand the role of trace elements and amino acids in the pathophysiology of nail psoriasis.