Minocycline-induced blue sclera and skin hyperpigmentation

Abstract

A 73-year-old man presented to the emergency department with lethargy and influenza-like symptoms. Incidentally, prominent blue sclera and blue-grey skin discolouration to the periorbital skin, pinnae, neck, upper and lower limbs, hands, feet, fingernails and toenails were noted. His general practitioner (GP) had previously ceased amiodarone, believing it to be the causative agent. A literature search confirms the side effects were likely due to minocycline, which the patient had been taking for 10 years. Long-term minocycline use is associated with scleral and skin hyperpigmentation, with no apparent adverse effect on ocular structure or function. The pigmentation may reverse with cessation of minocycline, or it may be permanent. Amiodarone may also cause skin hyperpigmentation, but scleral pigmentation is not a known association. This case report explores the side effect profiles of these two drugs, and highlights the potential for confusion regarding causative agents when used concurrently.

Background

Minocycline is commonly used to treat acne or rheumatoid arthritis. Cases of acquired hyperpigmentation of the sclera, pinna, gums, nail beds and teeth related to minocycline use have been reported in the literature, along with more serious side effects such as hypersensitivity reactions and autoimmune disorders. Amiodarone is a potent anti-arrhythmic agent, commonly used in the management of atrial fibrillation. Amiodarone is also known to cause hyperpigmentation of the skin along with ocular side effects. Scleral hyperpigmentation, however, is not a known side effect of amiodarone.

Case presentation

A 73-year-old man presented to the emergency department with lethargy and influenza-like symptoms. On examination, it was noted that his bilateral sclera and periorbital skin exhibited a symmetrical prominent blue-grey discolouration (figures 1 and 2).

Figure 1.

Blue sclera.

Figure 2.

Bilateral blue sclera.

In addition, the pinnae, neck, upper and lower limbs, hands, feet, fingernails and toenails were also tinted the same blue-grey colour (figure 3). On examination, visual acuity was normal with no reported visual changes. Conjunctival injection was not apparent and there was no proptosis. Pupil size was equal to normal pupillary reflex. Slit lamp examination showed a normal cornea, lens and anterior chamber. Funduscopy revealed a normal fundal reflex and optic disc without evidence of papilledema, neuritis or glaucomatous changes. No pathology of the retina or macula was identified.

Figure 3.

Hyperpigmentation of nail beds.

Past medical history included iron deficiency anaemia, chronic obstructive pulmonary disease (COPD), rheumatic heart disease and atrial fibrillation (AF). Drug history included minocycline 50 mg two times per day (which he had taken for 10 years to manage COPD), warfarin, digoxin, allopurinol, furosemide and gabapentin. He had ceased amiodarone 200 mg daily 5 years earlier, which he had taken for 5 years to manage AF. The patient stated the discolouration had been present for approximately 7 years and amiodarone had been stopped by his GP as it was thought to be responsible.

Investigations

Bedside observations were within normal range. Blood tests indicated iron deficiency anaemia (Hb 88 g/L, iron 6 umol/L, ferritin 161 ug/L, transferrin 2.4 g/L, transferrin saturation 9%, MCV 88fl). Renal function, creatinine, electrolytes and liver function tests were within normal range. Chest X-ray showed no abnormality.

Differential diagnosis

The primary diagnosis was viral illness and secondary diagnosis was iron deficiency anaemia. The patient was advised that minocycline was likely the causative agent for the severe scleral and skin discolouration. He was advised to cease minocycline and follow-up with his GP to discuss alternative management for his COPD.

Treatment

Ferric carboxymaltose 1000 mg was administered in the emergency department and he was advised to follow-up with his GP to investigate the cause of his iron deficiency anaemia.

Outcome and follow-up

A follow-up discussion with the patient’s GP revealed that, despite being informed of the likelihood of minocycline causing the side effects, the patient chose to continue with minocycline to manage his COPD. This was likely due to the fact that, while cosmetically disfiguring, the effects did not bother the patient and appeared to be benign with no detriment to health or visual acuity. Due to this, it is not known whether ceasing minocycline improved the adverse ocular and cutaneous effects in this patient.

Discussion

Minocycline is commonly used to treat acne or rheumatoid arthritis and, as with other tetracycline antibiotics, has some efficacy in COPD. Cases of acquired hyperpigmentation of the sclera, pinna, gums, nail beds and teeth related to minocycline use have been reported in the literature.^1–4 Minocycline has also been reported to cause discolouration of bone and internal organs.⁵

Incidence of hyperpigmentation related to minocycline use reportedly ranges from 2.4% to 14.8%,⁶ but has been suggested to occur in up to 50% of cases.^2. Minocycline is also associated with rare but serious side effects such as hypersensitivity syndromes, autoimmune hepatitis and lupus.⁷

Hyperpigmentation of skin and scleral discolouration have been reported with minocycline use and are thought to occur with long-term use at doses of greater than 100 mg, with dose and duration-related propensity.1 6 8 9

The exact mechanism by which ocular and skin hyperpigmentation occurs is unknown, but is thought to involve iron deposits in macrophages, quinone deposits, increased melanin and iron chelated minocycline degradation products.^{5 10}

There are four types of minocycline-induced hyperpigmentation; type I is blue-black discolouration caused by iron-chelates of minocycline, type II is blue-grey pigmentation related to quinone deposits and type III relates to melanogenesis and occurs on sun-exposed areas of skin.^{4 11–13} Type IV has recently been described and involves pre-existing scars, commonly on the back.¹⁰ The patient in this case presented with type III, exhibiting a typical example of hyperpigmentation of sun-exposed areas of skin.

Minocycline-induced scleral discolouration may be diffuse or localised to the temporal intrapalpebral area, and may be enhanced by UV exposure.^{4 6} Scleral discolouration is always associated with blue pigmentation to the nail beds and type III hyperpigmentation of the skin,⁴ as seen in this patient. Scleral pigmentation has been reported to be cosmetic and not known to affect vision or damage ocular structures.^{6 14}

Skin and scleral discolouration may take years to dissipate, if at all, and the speed and extent of resolution is thought to be dependent on initial severity.⁹

The patient’s GP identified amiodarone as the causative agent. A well-known side effect of amiodarone is blue-grey hyperpigmentation of sun-exposed areas of skin, commonly the face and limbs, affecting 4%–9% of patients following at least 20 months of treatment at doses of 400–800 mg per day.¹⁴Following cessation, full remission of skin hyperpigmentation may take several years due to the slow elimination of amiodarone and its metabolites from the tissues.¹⁴

Amiodarone is associated with ocular changes including corneal verticillata/vortex keratopathy, papilloedema, retinal haemorrhages, corneal and lens opacities and visual changes.^{5 9 15} However, the patient in this case study did not display these ocular changes and amiodarone has not been reported to induce blue sclera.

This case is interesting as both amiodarone and minocycline are known to cause skin hyperpigmentation, however it is not known whether amiodarone causes blue sclera. As this patient had ceased amiodarone 5 years earlier it is possible that skin hyperpigmentation was still in remission and not yet fully resolved. It would be useful to follow-up with this patient after a few years to see if there has been any resolution of skin and scleral hyperpigmentation, to help confirm which was the causative agent.

Learning points.

• Minocycline is associated with rare but significant side effects such as hyperpigmentation, hypersensitivity and autoimmune disorders.

• Minocycline can cause blue scleral discolouration and blue-grey skin hyperpigmentation.

• Amiodarone can cause blue-grey skin hyperpigmentation, but is not known to cause blue sclera.

• Clinicians need to be aware of the significant side effect profiles of these two medications, particularly when used concurrently.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).