Hyperpigmentation

Hyperpigmentation is darkening of the skin from increased melanin (epidermal or dermal) or from deposition of other pigments.

Classification by distribution

• Localised: melasma, postinflammatory hyperpigmentation, solar lentigines, freckles, café au lait macules, naevi, acanthosis nigricans, fixed drug eruption, phytophotodermatitis, friction melanosis, erythema ab igne.
• Generalised or diffuse: adrenal insufficiency, haemochromatosis, drugs, chronic liver and kidney disease, thyroid disease, nutritional deficiency, HIV.
• Patterned: flagellate (bleomycin), linear, reticulate.

Classification by depth. Epidermal pigment is brown with well defined margins and is enhanced under Wood lamp. Dermal pigment is blue grey with ill defined margins and is not enhanced. Mixed pigmentation shows both features.

Mechanisms. Increased melanocyte activity or number from ultraviolet light, hormones (ACTH and melanocyte stimulating hormone through the melanocortin 1 receptor, oestrogen, progesterone), inflammation, drugs, or increased melanin transfer to keratinocytes. Pigment incontinence into the dermis after inflammation causes persistent dermal pigmentation.

Skin of colour. Postinflammatory hyperpigmentation and melasma are very common and cause considerable distress. Irritation from treatments readily causes more pigment.

Key distinctions. Progressive darkening with fatigue and weight loss suggests Addison disease. Mucosal and palmar crease pigmentation suggests adrenal insufficiency or Peutz-Jeghers syndrome. A changing pigmented lesion needs exclusion of melanoma.

History

• Onset (sudden or gradual), site, spread, preceding rash or injury, sun exposure, photosensitivity, and symptoms such as itch.
• Pregnancy, oral contraceptive or hormone therapy, family history of pigment disorders.
• Drugs: minocycline (blue grey), amiodarone (slate grey on exposed sites), chlorpromazine, hydroxychloroquine, busulfan, cyclophosphamide, bleomycin, hydroxycarbamide, zidovudine, methotrexate, phenytoin, tetracyclines, NSAIDs (fixed eruption), 5-fluorouracil, psoralens.
• Cosmetics, perfumes, hair dyes, skin lightening products (hydroquinone, mercury, potent corticosteroids), plant contact (limes, figs, parsley), heat sources (hot water bottles, heaters), friction.
• Systemic symptoms: fatigue, weight loss, anorexia, nausea, abdominal pain, salt craving, postural dizziness (adrenal insufficiency); joint pain, diabetes, reduced libido (haemochromatosis); jaundice, itch (liver disease); cough, night sweats (tuberculosis); diarrhoea and neurological symptoms (pellagra).
• Past history of TB, HIV, liver disease, kidney disease, autoimmune disease, cancer.

Examination

• Pattern, colour, margin, texture (velvety in acanthosis nigricans), photodistribution, symmetry, surface change and scale.
• Mucosa (buccal, gums, tongue), palmar creases, scars, nipples, nails (longitudinal melanonychia).
• Blood pressure lying and standing.
• Signs of liver disease, hepatomegaly, thyroid enlargement, hypogonadism, joint disease (second and third metacarpophalangeal joints in haemochromatosis), cachexia.
• Dermoscopy for pigmented lesions and Wood lamp for depth.

Red flags

• A changing, asymmetric, irregular, multicoloured or enlarging pigmented lesion.
• New longitudinal pigmented nail streak in one digit, with widening or periungual pigment (Hutchinson sign).
• Hypotension, vomiting, abdominal pain, hyponatraemia, hyperkalaemia or hypoglycaemia with pigmentation (adrenal crisis).
• Rapid onset acanthosis nigricans in an adult with weight loss or mucosal involvement (malignancy, often gastric adenocarcinoma).
• Flagellate pigmentation after chemotherapy.
• Hepatomegaly, diabetes and arthropathy.
• Blue black pigmentation after skin lightening product use (exogenous ochronosis, mercury).
• Perioral lentigines with abdominal pain or bleeding (Peutz-Jeghers syndrome).

Special groups

• Children: café au lait macules (six or more over 5 mm before puberty, or over 15 mm after puberty, suggests neurofibromatosis type 1, particularly with axillary freckling), Mongolian blue spots, congenital naevi.
• Pregnancy: melasma, linea nigra and areolar darkening are physiological or hormonal. Avoid hydroquinone and retinoids.
• Older adults: solar lentigines, drug related pigmentation and malignancy.
• Region specific: skin lightening products, tuberculous adrenal disease, HIV associated pigmentation, pellagra and malnutrition.

Localised pigmentation

• Melasma.
• Postinflammatory hyperpigmentation.
• Solar lentigines and ephelides.
• Café au lait macules.
• Becker naevus.
• Congenital and acquired melanocytic naevi.
• Melanoma.
• Seborrhoeic keratosis.
• Acanthosis nigricans.
• Erythema ab igne.
• Friction melanosis.
• Phytophotodermatitis.
• Riehl melanosis (pigmented contact dermatitis).
• Lichen planus pigmentosus.
• Erythema dyschromicum perstans.
• Fixed drug eruption.
• Pityriasis versicolor.
• Confluent and reticulated papillomatosis.
• Macular and lichen amyloidosis.
• Stasis pigmentation and pigmented purpuric dermatoses.
• Dowling-Degos disease.
• Kaposi sarcoma.

Dermal and deposition pigmentation

• Naevus of Ota and Ito, Mongolian spot.
• Minocycline pigmentation.
• Amiodarone pigmentation.
• Chlorpromazine pigmentation.
• Argyria.
• Exogenous ochronosis (hydroquinone) and alkaptonuria.
• Tattoo and traumatic tattoo.
• Mercury and arsenic pigmentation.
• Haemosiderin deposition.

Generalised pigmentation

• Primary adrenal insufficiency (Addison disease).
• Nelson syndrome and ectopic ACTH syndrome.
• Haemochromatosis.
• Chronic liver disease and primary biliary cholangitis.
• Chronic kidney disease.
• Hyperthyroidism.
• Vitamin B12 and folate deficiency.
• Pellagra and kwashiorkor.
• HIV infection.
• Tuberculosis with adrenal involvement.
• Systemic sclerosis.
• POEMS syndrome.
• Porphyria cutanea tarda.
• Metastatic melanoma with melanosis.
• Drug induced diffuse pigmentation (busulfan, cyclophosphamide, zidovudine).

Syndromic and other

• Peutz-Jeghers syndrome.
• Neurofibromatosis type 1.
• McCune-Albright syndrome.
• Carney complex.
• Pregnancy related pigmentation.
• Carotenaemia and jaundice (yellow discolouration, mimic).

Step 1. Localised or generalised, epidermal or dermal. Use Wood lamp and dermoscopy. Consider pigmented skin cancer first for any asymmetric, changing or ulcerated lesion.

Step 2. Generalised or mucosal pigmentation

• Morning serum cortisol (8 to 9 am) with ACTH, electrolytes (low sodium, high potassium), glucose and renin with aldosterone. A cortisol under 100 nmol/L makes adrenal insufficiency very likely. A cortisol over 500 nmol/L excludes it. Intermediate values need a stimulation test: tetracosactide 250 micrograms intravenously or intramuscularly with cortisol at 0 and 30 minutes; a peak over about 500 nmol/L is normal (assay dependent). Oestrogen therapy raises total cortisol and can mislead.
• ACTH is high in primary adrenal insufficiency. Test 21 hydroxylase antibodies; if negative, adrenal CT for tuberculosis, haemorrhage or metastases.
• Ferritin and fasting transferrin saturation: ferritin over 300 micrograms/L in men (over 200 micrograms/L in women) with saturation over 45% suggests haemochromatosis, confirmed by HFE genotype (C282Y homozygosity). Liver tests, glucose and liver imaging or elastography.
• Liver tests, antimitochondrial antibody, urea, creatinine, TSH, free T4, B12, folate, full blood count, HIV test, urinary porphyrins, pregnancy test, ANA when scleroderma is suspected.
• Nutritional assessment for pellagra (niacin, tryptophan deficiency).

Step 3. Acanthosis nigricans. Fasting glucose or HbA1c, insulin, lipids, TSH, testosterone and sex hormone binding globulin (polycystic ovary syndrome). If onset is sudden in an adult, with weight loss or mucosal changes, investigate for malignancy (upper gastrointestinal endoscopy, CT).

Step 4. Skin biopsy. Excisional biopsy with a 2 mm margin for any lesion suspected to be melanoma (do not shave or partially biopsy). A 4 mm punch biopsy for diffuse or unclear dermal pigment, lichen planus pigmentosus, amyloidosis, ochronosis or deposition disorders. Fontana Masson stain highlights melanin and Perls stain highlights iron.

Step 5. Other tests. Patch testing for suspected Riehl melanosis or contact pigmentation. Genetic testing for neurofibromatosis type 1, McCune-Albright or Peutz-Jeghers syndrome in selected patients. Heavy metal levels for suspected mercury or arsenic.

Limits. Morning cortisol is unreliable during glucocorticoid treatment or in critical illness. Melasma and postinflammatory pigmentation are clinical diagnoses and need no tests in the absence of other features. Dermoscopy cannot exclude all melanomas.

Immediate: adrenal crisis. Hydrocortisone 100 mg intravenously or intramuscularly immediately, then 200 mg over 24 hours by continuous intravenous infusion (or 50 mg intravenously every 6 hours). Give 0.9% sodium chloride 1000 mL over the first hour, then continue by volume status. Check glucose and give dextrose if hypoglycaemic. Take cortisol and ACTH before treatment if this does not delay it. Admit.

Primary adrenal insufficiency (long term). Hydrocortisone 15 to 25 mg orally daily in 2 to 3 divided doses (for example 10 mg on waking, 5 mg at midday, 5 mg in the early afternoon). Fludrocortisone 50 to 300 micrograms orally once daily (usual 100 micrograms), adjusted to blood pressure, postural drop and electrolytes. Sick day rules: double or triple the hydrocortisone dose for fever or illness.

Give hydrocortisone 100 mg intramuscularly for vomiting or collapse, and teach self injection. Provide a steroid card and alert bracelet. Review pigmentation as the disease is controlled. Treat the cause (antituberculous therapy when tuberculous).

Haemochromatosis. Venesection of 450 to 500 mL weekly or fortnightly until ferritin reaches 50 micrograms/L, then maintenance venesection every 2 to 4 months to keep ferritin at 50 to 100 micrograms/L. Check haemoglobin before each session (defer when under 11 g/dL). Avoid iron and vitamin C supplements, limit alcohol, avoid raw shellfish, and screen first degree relatives. Monitor liver tests, glucose and cardiac and endocrine complications.

Melasma and postinflammatory hyperpigmentation

• Broad spectrum sunscreen of SPF 50 or more, tinted with iron oxides, applied every morning and reapplied every 2 hours outdoors, with a hat. This is the basis of treatment.
• Triple combination cream (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) applied nightly for up to 8 weeks under specialist direction, then a maintenance regimen.
• Hydroquinone 2 to 4% applied to the affected area twice daily for up to 3 to 4 months, then a break. Prolonged use or concentrations over 4% risk exogenous ochronosis, especially in darker skin.
• Azelaic acid 15 to 20% twice daily (safe in pregnancy).
• Tretinoin 0.025 to 0.05% or adapalene 0.1% at night; irritation worsens pigment in darker skin, so introduce gradually.
• Refractory melasma (specialist): tranexamic acid 250 mg orally twice daily for 3 to 6 months. Contraindicated in a history of thrombosis, active thromboembolic disease, concurrent oestrogen therapy and pregnancy.
• Chemical peels (glycolic acid 30 to 50%) and lasers have a high risk of postinflammatory pigmentation in darker skin and need experienced operators.
• Stop oestrogen containing contraceptives when they appear to drive melasma.
• Avoid mercury containing creams and potent corticosteroid lightening products, which cause atrophy, acne, adrenal suppression and ochronosis.
• Pregnancy and breastfeeding: sunscreen and azelaic acid only; avoid hydroquinone and retinoids.

Other causes

• Drug induced pigmentation: stop or replace the drug when possible. Fading takes months to years, and minocycline and amiodarone pigment may persist.
• Fixed drug eruption: stop the drug and record the allergy.
• Pityriasis versicolor: ketoconazole 2% shampoo to the affected skin daily for 5 to 7 days, or itraconazole 200 mg orally once daily with food for 7 days (monitor liver tests; avoid in heart failure; many CYP3A4 interactions; not in pregnancy). Pigment changes may persist for weeks to months after clearance.
• Acanthosis nigricans: weight loss and treatment of insulin resistance. Metformin 500 mg orally once daily with food, increased weekly to 1 to 2 g daily in 2 divided doses (maximum 2 g daily; reduce to 1 g daily when eGFR is 30 to 44 mL/min/1.73 m2; stop when under 30; monitor vitamin B12). Topical tretinoin or urea 10% for texture.
• Erythema ab igne: remove the heat source and observe for skin cancer over the long term.
• Phytophotodermatitis and friction melanosis: avoid the trigger; fading takes weeks to months.
• Stasis pigmentation: compression therapy.
• Pigmented skin cancer: excision with margins and staging by oncology.
• Syndromic disease: specialist surveillance (for example gastrointestinal polyp surveillance in Peutz-Jeghers syndrome).

Monitoring. Review at 8 to 12 weeks with photographs. For adrenal insufficiency: symptoms, weight, postural blood pressure, sodium and potassium. For haemochromatosis: ferritin, transferrin saturation and liver tests. Skin checks for melanoma risk.

Referral and escalation

• Same day endocrinology or acute medical review for suspected adrenal insufficiency with symptoms.
• Dermatology within 2 weeks for suspected melanoma.
• Hepatology and haematology for haemochromatosis.
• Gastroenterology and oncology for suspected malignancy associated acanthosis.
• Genetics for neurofibromatosis, McCune-Albright and Peutz-Jeghers syndromes.
• Dermatology for refractory melasma, ochronosis and persistent dermal pigmentation.

Admission criteria. Adrenal crisis, hypotension, sodium under 125 mmol/L, potassium over 6 mmol/L, or severe vomiting.

Discharge and follow up. Safety net advice: return for a changing mole, dizziness, vomiting, abdominal pain, weight loss, or new pigmentation with fatigue.