Rapidly Progressive Facial Hyperpigmentation as a Cutaneous Marker of Acute-on-Chronic Liver Failure

Dear Editor,

A 45-year-old male presented with complaints of facial hyperpigmentation for the past 7 days. He had been a known case of liver cirrhosis for 3 years and had been admitted to the intensive care unit 14 days prior for acute decompensation. He had a history of chronic alcohol consumption for the past 20 years. He had no other significant comorbidities.

During hospitalisation, he developed progressive, isolated facial hyperpigmentation. Cutaneous examination revealed diffuse brownish pigmentation over the centrofacial region, including the periorbital areas, nose, cheeks and chin, with mild scaling and partial sparing of the peripheral facial skin [Figure 1]. There was no involvement of the mucosae, palmar creases, knuckles or other body sites. Other than this, he had bilateral icterus, mild generalised yellowish discolouration and xerosis of skin, malar prominence and mild temporal hollowing also. There was marked loss of subcutaneous fat, giving a thin, wasted appearance. Other features of chronic liver disease (CLD) such as spider angiomas, palmar erythema, gynaecomastia, caput medusae and parotid gland enlargement were not present in our patient. On general and systemic examination, he had bilateral pedal oedema and gross ascites.

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Figure 1: Diffuse brownish pigmentation over the centrofacial region (white circle- site of biopsy).

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Laboratory investigations showed significantly deranged liver function tests: Alanine aminotransferase 175 IU/L, aspartate aminotransferase 212 IU/L, total bilirubin 11.5 mg/dL, prothrombin time 22 s and international normalised ratio 2.8. He was moderately anaemic (haemoglobin 7.9 g/dL). Other relevant parameters, including serum urea, creatinine, sodium, vitamin B12, iron profile including serum iron, transferrin, serum ferritin levels, copper, ceruloplasmin and 24-h urinary copper levels, were within normal limits. Serological tests for Hepatitis B and Hepatitis C were negative. Due to acute decompensation, anti-hepatitis A virus and anti-hepatitis E virus were also tested, which were also negative.

The patient had been receiving intravenous antibiotics for 7 days, none of which are known to cause cutaneous hyperpigmentation. A punch biopsy from the right cheek demonstrated increased basal layer pigmentation with mild pigment incontinence in the papillary dermis, without any significant dermal inflammatory infiltrate [Figure 2a and b].

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Figure 2: (A) (Haematoxylin and eosin (H and E) ×4) - Increased basal layer pigmentation (black arrows) with minimal dermal infiltrate(red curved arrow), (B) (H and E ×20) - Mild pigment incontinence in the papillary dermis (black circles).

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Based on the clinical presentation, histopathological findings and temporal association with hepatic decompensation, a diagnosis of facial hyperpigmentation secondary to acute-on-chronic liver failure was made. The patient was counselled and managed for his underlying hepatic condition.

CLD is a global health problem associated with a plethora of dermatological manifestations such as pruritus, icterus, spider angiomas, palmar erythema, xanthelasma, pigmentary, nail changes and nutritional deficiencies.^[1] The most common manifestations are largely nonspecific, comprising pruritus, icterus, pigmentary and nail changes and ichthyosis.^[2,3] Pigmentary changes in CLD have been described as muddy grey coloured hyperpigmentation predominantly over sun-exposed areas which may be blotchy or diffuse with occasional exacerbation at perioral, periocular areas and palmar creases or as pigmented spots on the abdomen, back, hands and feet.^[1] Mucosal pigmentation is also found in many cases.^[2] In a case series, 55% of patients showed pigmentary changes – 40% with hyperpigmentation and 24% with guttate hypopigmentation. Guttate hypopigmentation was mainly seen on the abdomen, back and lower limbs.^[3] Worsening of hyperpigmentation is associated with acute failure on CLD.^[4,5] The facial involvement in CLD is often referred to as ‘hepatic face’, characterised by dull appearance, shrunken eyes, periorbital pigmentation, dryness, rough skin texture, poor elasticity, temporal hollowing, parotid enlargement and malar prominence.^[4] The exact mechanism of facial hyperpigmentation remains unclear. However, excessive reactive oxygen species (ROS) that leads to hepatocyte damage promote cytokine release, such as tumour necrosis factor - alpha and IL-6, which further exacerbate liver damage, creating a vicious cycle. These ROS and inflammatory cytokines such as IL-1a, IL-10, IL-18 and IL-33 modulate both liver fibrosis and melanin production by activating signalling pathways such as nuclear factor - kappa, PI3K/AKT (Phosphatidylinositol 3-Kinase and Protein Kinase B) and nuclear factor erythroid 2-related factor 2.^[4] In patients with cirrhosis, plasma oestrogen levels are higher than those in control groups which has been hypothesised to cause excess melanin production similar to chloasma observed during pregnancy.^[4] Other hypotheses include increased melanocyte melanin production, faster melanosome transfer to keratinocytes, larger melanosomes and defective melanin degradation in lysosomes.^[6] Other causes of hyperpigmentation in the clinical setting of CLD include hemochromatosis, Wilson’s disease and nutritional deficiency and should be ruled out with relevant investigations. The reason for isolated facial involvement during decompensation remains unclear. With respect to treatment and response, there is a paucity of data in the literature to ascertain whether pigmentation improves with management of primary liver disease or with antioxidants, which may decrease oxidative stress.^[4]

Our case highlights the unique presentation of decompensating liver disease with rapidly progressive diffuse facial hyperpigmentation, and identifying this common clinical manifestation can help in early diagnosis and timely management of worsening liver disease and associated mortality.