The peculiar case of a blue man.

Sir,

A 53-year-old male patient was admitted to our hospital with alcoholic hepatitis and hepatic encephalopathy. He was mildly confused at the time of admission which precluded a detailed history including medication history. Physical examination revealed a prominent bluish discoloration of his skin with icteric conjunctiva and generalized edema. Pulse and blood pressure were normal and pulse oximetry saturations ranged between 91% and 94% at room temperature. The bluish discoloration was noted over the face, trunk and legs [Figures 1 and 2]. Differential diagnosis considered are enumerated in Table 1. Multiple scarred bluish pigmented acneiform lesions were also noted over the back. There was ascites without organomegaly. A blood gas analysis revealed normal oxygen and CO2 levels and methemoglobin content was within normal limits. A detailed review several days later revealed that the patient was taking 100 mg of Minocycline daily for last 3 years for treatment of acne (cumulative dose of approximately 11 grams). His laboratory investigations revealed a normal ceruloplasmin and morning cortisol levels. A liver biopsy excluded hemosiderosis.

Figure 1

Photograph of the patients face shows a diffuse fixed bluish discoloration over his face, similar discoloration was noted over the entire trunk

Figure 2

A spotted as well as confluent pattern of hyperpigmentation was most prominent over anterior aspect of both legs

Table 1

Enumerating the differential diagnosis of bluish hyperpigmentation of the skin after exclusion of cyanotic causes

Drug-induced hyperpigmentation	Chloroquine, amiodarone, doxorubicin, phenothiazine, minocycline, bismuth and hydroxychloroquine[1]
Drug-induced methemoglobinemia	Dapsone, aniline dyes, lidocaine and benzocaine
Argyria and chrysiasis	Gold and silver toxicity respectively[1]
Metabolic diseases	Hemochromatosis, alkaptonuria, Addison's disease, and Wilson's disease

A skin biopsy revealed dark, nearly black pigment deposition within macrophages. This again correlated with minocycline-induced hyperpigmentation. Minocycline is a synthetic tetracycline with a prolonged half-life of (t1/2 of 15.5 hours). It is used for the treatment of moderate to severe acne and as a disease modifying agent for treatment of rheumatoid arthritis and osteoarthritis. Long-term use of minocycline in cumulative doses of greater than 100 grams have been known to be associated with pigmentation, although smaller doses can also result in mucosal pigmentation.[2] The prevalence of hyperpigmentation after treatment for 10.5 months among 700 patients was 0.4% at a dose of 100 mg/day and 4% at 200 mg/day.[3] Another study revealed that 2.4% to 14.8% of patients taking minocycline chronically for acne or rosacea developed hyperpigmentation.[4] This hyperpigmentation is of three types. Our patient had type II lesions on the legs which are well-circumscribed lesions characteristically seen on healthy skin [Figure 2]. Type III is a diffuse hyperpigmentation over sun-exposed areas as seen over the face and these are less likely to respond to laser therapy [Figure 1].[5] Lesions on the back might infrequently appear that resemble Type I lesions developing within acne scars.[4] Type I lesions are bluish-black macules that develop over acneiform lesions on the face.[6] Although unclear, possible mechanisms for this pigmentation include siderosis, deposition of insoluble complexes of minocycline or its derivatives chelated to iron, melanin or calcium.[46] The patient was offered Alexandrite™ laser therapy but refused treatment because of his chronic ill health and decompensated alcoholic liver disease. Alexandrite lasers (755-nm), Nd:YAG (532-/1064-nm) and Ruby(694-nm) lasers have been reported to help resolution of all types ofminocycline-induced hyperpigmentation. It is hypothesized that the laser fragments the intracellular and extracellular pigments and aids in their drainage through the lymphatics.[7] Laser adverse effects are limited to mild desquamation and transient purpura without significant lasting hypopigmentation or scarring.[78] It is important to periodically check for pigmentation among patients on minocycline to prevent cosmetic disfigurement. Estrogen preparations, phenothiazines and amitriptyline that have the propensity to potentiate pigmentation and thus co-therapy is best avoided.[9] Sunlight has also been known to aggravate hyperpigmentation and sunscreens with high SPF are recommended.[10]

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