A 42-year-old man of Punjabi descent presents with a 6-month history of recurrent blistering and erosions on the dorsal surfaces of his hands and forearms, worse in summer. He also reports progressive darkening of urine and mild hepatomegaly on examination. Serum transaminases are mildly elevated (ALT 1.5× ULN). Urine porphyrins are elevated, and plasma porphyrins are normal. Which enzyme deficiency is responsible for this condition?

Explanation

## Diagnosis: Porphyria Cutanea Tarda (PCT) — Enzyme Deficiency ### Clinical Presentation of PCT This patient presents with the classic features of **porphyria cutanea tarda (PCT)**: - **Photosensitive blistering**: on sun-exposed areas (dorsal hands, forearms, face, neck) - **Chronic cutaneous manifestations**: erosions, scarring, hyperpigmentation, skin fragility - **Urine darkening**: due to elevated uroporphyrin (dark red-brown) - **Liver involvement**: mild hepatomegaly, elevated transaminases (often associated with HCV or alcohol) ### Enzyme Defect: Uroporphyrinogen Decarboxylase (UROD) Deficiency **Key Point:** PCT results from deficiency of **uroporphyrinogen decarboxylase (UROD)**, the fifth enzyme in heme synthesis. This causes: - Accumulation of **uroporphyrinogen III** and **uroporphyrin III** - Elevated **urine porphyrins** (uroporphyrin > coproporphyrin) - **Normal plasma porphyrins** (distinguishes PCT from erythropoietic protoporphyria) - Photosensitivity due to porphyrin-mediated free radical generation in skin ### Types of PCT | Type | Inheritance | Enzyme Level | Trigger | |------|-------------|--------------|----------| | **Type I (85%)** | Acquired | Low in liver only | Alcohol, HCV, estrogens, iron | | **Type II (10%)** | Autosomal dominant | Low in all tissues | Genetic UROD mutation | | **Type III (5%)** | Sporadic | Low in liver | Unknown | **High-Yield:** Type I PCT is the most common form and is acquired, often triggered by hepatitis C, alcohol, or estrogen use. It is NOT inherited. ### Diagnostic Laboratory Features | Test | PCT | AIP | EPP | |------|-----|-----|-----| | **Urine porphyrins** | ↑↑ (uro > copro) | ↑ ALA & PBG | Normal | | **Plasma porphyrins** | Normal | Normal | ↑↑ Protoporphyrin | | **Stool porphyrins** | ↑ Coproporphyrin | Normal | ↑↑ Protoporphyrin | | **Acute attacks** | No | Yes | No | | **Photosensitivity** | Yes (chronic) | No | Yes (acute pain) | **Clinical Pearl:** The combination of **elevated urine porphyrins + normal plasma porphyrins + chronic photosensitivity** is diagnostic of PCT and distinguishes it from erythropoietic protoporphyria (which has elevated plasma porphyrins). ### Pathophysiology of Photosensitivity in PCT Uroporphyrin absorbs light at 400–410 nm (Soret band), generating singlet oxygen and free radicals that damage skin collagen and cause: - Blistering and erosions - Scarring and hyperpigmentation - Skin fragility ("tissue paper" skin) ### Management 1. **Avoid triggers**: alcohol, estrogens, iron supplements, HCV 2. **Screen and treat HCV**: present in ~50% of Type I PCT 3. **Phlebotomy**: removes iron, reduces hepatic UROD inhibition 4. **Low-dose hydroxychloroquine**: mobilizes hepatic porphyrins 5. **Sun protection**: broad-spectrum sunscreen **Mnemonic:** **PCT = Photosensitivity + Cutaneous + Uroporphyrin** (urine porphyrins elevated, plasma normal) [cite:Robbins 10e Ch 7; Harrison 21e Ch 297]