What are the typical clinical presentation, precipitating factors, and management strategies for porphyria cutanea tarda in adult women?

Porphyria Cutanea Tarda: Clinical Presentation and Management

Clinical Presentation

Porphyria cutanea tarda (PCT) typically presents in adults during the 5th to 6th decade of life with characteristic skin fragility and blistering lesions on sun-exposed areas, particularly the hands and face. 1

Cutaneous Manifestations

• Bullae, hyperpigmentation, and erosions develop on sun-exposed areas such as hands and face 1
• Increased skin fragility with blistering that can range from mild to severe, with some patients describing "skin falling off" and feeling as if in a "horror movie" 2
• Hypertrichosis (excessive hair growth), particularly malar hypertrichosis, occurs in many patients 3, 4
• Milia formation (small white cysts) may develop at sites of previous blistering 3
• Sclerodermatous changes can occur, mimicking morphea on the neck, neckline, and face, sometimes without typical blistering 4
• Pruritus can be severe enough to prevent sleep and delay healing 2

Urine Appearance

• Urine appears red to brown in natural light and pink to red under fluorescent light, providing a valuable diagnostic clue 3

Systemic Features

• Mild liver enzyme elevations are common, though only approximately 13% show elevated transaminases during active disease 5
• Advanced fibrosis, cirrhosis, and hepatocellular carcinoma can occasionally develop 6

Precipitating Factors

PCT requires uroporphyrinogen decarboxylase (URO-D) deficiency plus additional susceptibility factors to manifest clinically. 1, 6

Major Triggers

• Iron overload with or without HFE gene mutations (H63D, C282Y) 6, 7
• Alcohol abuse is a frequent precipitant 6, 3, 4
• Hepatitis C virus (HCV) infection has a demonstrated pathogenetic role, particularly in certain geographical areas 1, 6
• HIV infection 6
• Estrogen use (oral contraceptives, hormone replacement therapy) 2, 6
• Smoking 6
• Certain medications, including hydroxychloroquine in susceptible individuals 7

Disease Subtypes

• Sporadic PCT (most common): URO-D activity decreased to 50% in hepatocytes only, usually non-hereditary 1
• Familial PCT (Type II): Autosomal dominant UROD mutation present in all cells, but still requires additional susceptibility factors to manifest 1, 6

Diagnostic Approach

Diagnosis requires biochemical confirmation through demonstration of elevated serum and urinary porphyrins, with biochemical testing mandatory before any genetic testing. 1

Essential Diagnostic Tests

• 24-hour urine porphyrin measurement showing elevated uroporphyrins confirms the diagnosis 1, 3
• Serum porphyrin levels should be measured 1
• URO-D enzyme activity demonstrates deficiency 1
• Skin biopsy of bullous lesions can help rule out other blistering disorders but may show features of morphea/scleroderma in sclerodermatous variants 3, 4

Additional Workup

• Screen for hepatitis C and possibly hepatitis B, especially in patients under 30 years with extremely high transaminase levels 3
• Assess iron stores (ferritin, transferrin saturation) 6, 3
• HFE gene testing for hemochromatosis mutations 6, 7
• Liver function tests and evaluation for underlying liver disease 1, 4
• Blood glucose as levels are often elevated 3

Important Diagnostic Caveat

Genomic testing should not be used for diagnostic screening without prior biochemical confirmation of elevated porphyrin-related markers, as PCT is usually sporadic and non-hereditary. 1

Management Strategies

Treatment consists of either repeated phlebotomy or low-dose hydroxychloroquine (100 mg orally twice weekly), both equally effective and safe. 6

First-Line Therapeutic Options

Phlebotomy

• Repeated phlebotomy to reduce iron stores is highly effective 6, 3
• Continue until iron stores are depleted and porphyrin levels normalize 6
• May have lower relapse rates compared to hydroxychloroquine in some observational data 6

Low-Dose Hydroxychloroquine

• 100 mg orally twice weekly (not daily dosing) increases urinary porphyrin excretion 2, 6
• Equally effective as phlebotomy 6
• Caution: Standard doses can cause hepatotoxicity; low-dose regimen is essential 7
• Can be used for porphyrin clearance even in patients with autoimmune conditions requiring immunosuppression 7

Conservative Measures (Essential for All Patients)

• Strict avoidance of ultraviolet light exposure and use of sun protection 3
• Complete alcohol abstinence 3, 4
• Discontinue estrogen-containing medications 3
• Avoid triggering medications 3

Management of Underlying Conditions

• Treat hepatitis C infection with direct antiviral agents, which may benefit both PCT and HCV 6
• Address iron overload through phlebotomy or chelation if indicated 6
• Manage concurrent liver disease (cirrhosis, fatty liver) 4

Long-Term Monitoring

• Surveillance with liver ultrasound and α-fetoprotein every 6 months is recommended for hepatocellular carcinoma screening, especially in patients with cirrhosis or advanced fibrosis 5, 6
• Monitor for relapse, particularly when susceptibility factors are not adequately controlled 6
• Relapse rates may be somewhat higher after hydroxychloroquine-induced remission compared to phlebotomy, though data are limited 6

Treatment Response

• Complete normalization of porphyrin levels is achievable in most patients with appropriate treatment 4
• Skin lesions typically resolve completely or show partial improvement with treatment and porphyrin normalization 4
• Sclerodermatous changes may regress with normalization of porphyrin levels 4