Tongue hyperpigmentation during interferon-alpha and ribavirin therapy

ARTICLE

Auteur(s) : Ingrid Aguayo-Leiva, Bibiana Pérez, Irene Salguero, Pedro Jaén

Department of Dermatology, Hospital Ramón y Cajal, Carretera Colmenar Viejo Km 9100 Madrid, Spain

Cutaneous hyperpigmentation may be caused by a number of primary cutaneous and systemic diseases, such as Addison’s disease, haemochromatosis, metastatic melanoma and scleroderma, and a whole spectrum of drugs, such as oral contraceptives, cyclophosphamide, bleomycin, chloroquine, minocycline, ketoconazole, methyldopa, and antidepressants. In HIV-infected patients, this skin disorder has been described with the use of zidovudine, pyrimethamine or spyramycin [1]. Well-known cutaneous side effects of interferon (IFN) or PEG-interferon alfa (PEG-INF) include dry skin, pruritus, hair loss, and psoriasis. Skin hyperpigmentation related to antiviral therapy for chronic hepatitis C (HCV) is rare. Gurguta et al. [2] described the first report of tongue hyperpigmentation during PEG-INF and ribavirin combination therapy in five non-white patients with HCV infection; the only risk factor for this complication seemed to be the dark skin colour. We describe oral mucosa and tongue hyperpigmentation in a Caucasian woman during PEG-INF-2α and ribavirin therapy. To our knowledge, only one case of tongue hyperpigmentation in a Caucasian HCV-mono-infected patient has previously been reported in the literature [3].

A 54-year-old Caucasian woman was referred for incidental detection of chronic hepatitis C (genotype 1b). A liver biopsy showed severe fibrosis and early nodule formation. Treatment was initiated with PEG-INF-2α 80 mg and oral ribavirin 800 mg daily. About 4 months after starting treatment she noticed numerous asymptomatic dark macules on her tongue and oral mucosa. The pigmentation gradually increased till completion of the treatment. Physical examination showed a brown macular pigmentation on the tongue surface and brown irregular spots were also observed on the oral mucosa (figures 1A, B). Laboratory evaluation showed serum alanine aminotransferases were 201 UL^-1 (normal ≤ 31UL^-1) and serum aspartate aminotransferases 205 UL^-1(normal ≤ 112 UL^-1), other parameters, including vitamin B12, cortisol and thyroid-stimulating hormone were within normal limits. Human immunodeficiency virus (HIV) and the use of other drugs associated with tongue hyperpigmentation were excluded. Hyperpigmentation persisted during the therapy.

HCV is capable of inducing cutaneous diseases. The association between chronic HCV infection and porphyria cutanea tarda, lichen planus and cutaneous necrotizing vasculitis are well known. Many types of adverse skin reactions have also been described during INF monotheraphy for chronic HCV infection. Transient alopecia, vasculitis and exacerbation of autoimmune diseases such as psoriasis, lichen planus or vitiligo have been reported [4]. Combination therapy with INF and ribavirin induces more skin reactions than INF alone, suggesting a synergistic effect between INF and ribavirin. These cutaneous adverse reactions were predominantly of a lichenoid type [4]. Other observed reactions are eczema, erythema and rash [1, 5]. To our knowledge, less than 15 cases of INF-induced tongue hyperpigmentation have been reported, usually in non-white HCV mono-infected patients. Fernandez et al. [3] report the first case in a Caucasian HCV-mono-infected patient. The temporal relation between beginning HCV therapy and tongue hyperpigmentation, along with the lack of an alternative explanation for the observed pigmentary changes, made us speculate that PEG-INF-2α and ribavirin therapy induced this abnormality. The mechanism is unknown, but the INF could be upregulating melanocyte-stimulating hormone receptors, this would increase melanin production leading to hyperpigmentation. A contributing role of ribavirin can not be excluded [1, 6]. A biopsy confirmed the presence of foci with slightly increased numbers of melanocytes in the basal layer of the epithelium, in the cases reported by Willems et al. [1]. Tongue hyperpigmentation occurs mostly after months of therapy (1-10 months) and usually improves or disappears slowly after the end of the therapy, thus discontinuation is not recommended [3, 6].

In summary, tongue hyperpigmentation in HCV therapy has started to be reported in Caucasian patients, suggesting that it is equally prevalent as in darker skin.

Acknowledgements

Références

2 Gurguta C, Kauer C, Bergholz U, Formann E, Steindl-Munda P, Ferenci P. Tongue and skin hyperpigmentation during PEG-interferon-alpha/ribavirin therapy in dark-skinned non-Caucasian patients with chronic hepatitis C. Am J Gastroenterol 2006; 101: 197-8.

3 Fernández A, Vázquez S, Rodríguez-González L. Tongue hyperpigmentation resulting from peginterferon alfa-2a and ribavirin treatment in a Caucasian patient with chronic hepatitis C. J Eur Acad Dermatol Venereol 2008: 18.

4 Sookoian S, Neglia V, Castaño G, Frider B, Kien MC, Chohuela E. High prevalence of cutaneous reactions to interferon alfa plus ribavirin combination therapy in patients with chronic hepatitis C virus. Arch Dermatol 1999; 135: 1000-1.

5 Sood A, Midha V, Bansal M, Goyal A, Sharma N. Lingual hyperpigmentation with pegylated interferon and ribavirin therapy in patients with chronic hepatitis C. Indian J Gastroenterol 2006; 25: 324.

6 Torres HA, Bull L, Arduino RC, Barnett BJ. Tongue hyperpigmentation in a caucasian patient coinfected with HIV and hepatitis C during peginterferon alfa-2b and ribavirin therapy. Am J Gastroenterol 2007; 102: 1334-5.