A 35-year-old man of Gujarati descent presents with a 2-week history of progressive blistering and erosions on the dorsal surfaces of his hands and forearms, triggered by sun exposure. He reports chronic alcohol use (40 units/week). On examination, he has skin fragility, hyperpigmentation, and hypertrichosis on the affected areas. Liver function tests show mild elevation of transaminases (ALT 1.5× ULN) and elevated ferritin (450 ng/mL). Urine porphyrins are normal, but fecal porphyrins are markedly elevated. Which enzyme deficiency underlies this condition?

Explanation

## Diagnosis: Porphyria Cutanea Tarda (PCT) ### Clinical Presentation **Key Point:** Porphyria cutanea tarda is the most common porphyria (~80% of all porphyrias) and presents exclusively with **chronic photosensitivity** — not acute neurovisceral attacks. ### Classic Features of PCT | Feature | Presentation | |---------|---------------| | **Skin findings** | Blistering, erosions on dorsal hands/forearms (sun-exposed areas) | | **Fragility** | Skin fragility with minor trauma ("fragilitas cutis") | | **Hyperpigmentation** | Increased pigmentation in affected areas | | **Hypertrichosis** | Abnormal hair growth on face/forearms | | **Scarring** | Atrophic scars and milia formation | | **Photosensitivity** | Triggered by UVA exposure | | **Acute attacks** | **ABSENT** — distinguishes PCT from acute porphyrias | **Clinical Pearl:** PCT is the **only porphyria with cutaneous manifestations but NO acute neurovisceral attacks**. This is a key discriminator in NEET PG exams. ### Biochemical Basis: Uroporphyrinogen Decarboxylase (UROD) Deficiency **High-Yield:** PCT results from deficiency of **uroporphyrinogen decarboxylase (UROD)**, the fifth enzyme in the heme synthesis pathway. ```mermaid flowchart TD A[Heme synthesis pathway]:::action --> B[Uroporphyrinogen III]:::outcome B --> C[UROD enzyme]:::action C -->|Normal| D[Coproporphyrinogen III]:::outcome C -->|Deficient| E[Uroporphyrin accumulates]:::urgent E --> F[Uroporphyrin deposits in skin]:::outcome F --> G[Photosensitivity on UVA exposure]:::outcome ``` ### Two Types of PCT | Type | Inheritance | Enzyme Level | Prevalence | Risk Factors | |------|-------------|--------------|-----------|---------------| | **Type 1 (sporadic)** | Sporadic | UROD ↓ in liver only | 80% | Alcohol, hepatitis C, HIV, estrogens | | **Type 2 (familial)** | Autosomal dominant | UROD ↓ in all tissues | 20% | Family history of porphyria | | **Type 3** | Sporadic | UROD ↓ in liver | Rare | Associated with hepatitis C | **Mnemonic:** **PCT = UROD deficiency + Hepatic triggers** - **P**orphyria **C**utanea **T**arda - **U**roporphyrinogen **D**ecarboxylase deficiency - **R**ole of liver (Type 1 enzyme deficiency is hepatic) - **O**xidative stress (alcohol, iron overload worsen disease) - **D**ark urine is **NOT** a feature (urine porphyrins are normal) ### Diagnostic Laboratory Findings **Key Point:** The diagnostic hallmark is **elevated fecal porphyrins with NORMAL urine porphyrins** — this is pathognomonic for PCT. | Test | PCT | AIP | EPP | VP | |------|-----|-----|-----|----| | **Urine PBG** | Normal | ↑↑ (acute) | Normal | ↑ (acute) | | **Urine ALA** | Normal | ↑↑ (acute) | Normal | ↑ (acute) | | **Fecal porphyrins** | ↑↑ (uroporphyrin) | Normal/↑ | Normal | ↑↑ | | **Plasma porphyrins** | Normal | Normal | ↑↑ | ↑ | | **Photosensitivity** | Yes (UVA) | No | Yes (burning) | Yes (blistering) | | **Acute attacks** | No | Yes (severe) | No | Yes (mild) | ### Risk Factors and Triggers in This Patient **Clinical Pearl:** This patient has **Type 1 PCT** (sporadic) with multiple hepatic triggers: 1. **Chronic alcohol use** — major trigger; increases oxidative stress and iron absorption 2. **Elevated ferritin** — iron overload exacerbates UROD inhibition 3. **Liver dysfunction** (mild transaminitis) — hepatic UROD deficiency 4. **Possible hepatitis C or HIV** — common comorbidities in PCT ### Pathophysiology of Photosensitivity 1. Uroporphyrin accumulates in the skin (especially in dermal blood vessels) 2. UVA exposure (300–400 nm) excites uroporphyrin to singlet state 3. Singlet uroporphyrin transfers energy to oxygen → reactive oxygen species (ROS) 4. ROS cause lipid peroxidation, collagen damage, and blistering 5. Repeated cycles → scarring, hypertrichosis, hyperpigmentation ### Management of PCT 1. **Phlebotomy** — first-line therapy; removes iron and triggers remission - Target: Ferritin <50 ng/mL or hemoglobin just above anemia threshold - Frequency: 500 mL every 1–2 weeks until remission 2. **Low-dose hydroxychloroquine** — alternative if phlebotomy contraindicated - Mechanism: Mobilizes hepatic uroporphyrin for urinary excretion - Dose: 100–200 mg twice weekly (avoid higher doses — risk of hepatotoxicity) 3. **Avoid triggers:** Alcohol cessation, sun protection (UVA blockers), avoid estrogens 4. **Screen for comorbidities:** Hepatitis C, HIV, hemochromatosis **Warning:** Do NOT use high-dose hydroxychloroquine (>200 mg/day) in PCT — risk of acute hepatotoxicity and porphyrin mobilization crisis. ### Why This Patient Has PCT (Not AIP or Others) - **Chronic photosensitivity** (blistering on sun-exposed areas) is the hallmark — rules out AIP (no photosensitivity) and EPP (different photosensitivity pattern) - **Normal urine porphyrins + elevated fecal porphyrins** is pathognomonic for PCT - **No acute abdominal or neuropsychiatric symptoms** — distinguishes from AIP and VP - **Risk factors present:** Alcohol, iron overload, liver disease — all classic for Type 1 PCT - **UROD deficiency** in the liver explains the hepatic triggers and reversibility with phlebotomy **High-Yield:** PCT is the only porphyria where **phlebotomy** is the definitive treatment — this is a frequently tested fact in NEET PG.