A 35-year-old Indian man presents with a 2-year history of progressive photosensitivity, blistering on the dorsal surfaces of hands and face, and hyperpigmentation. He has a history of hepatitis C infection and mild hepatic dysfunction. Serum transaminases are mildly elevated. Urine shows increased uroporphyrin (predominantly Type III isomer). Faecal porphyrins are also elevated. Which enzyme deficiency is responsible for this condition?

Explanation

## Diagnosis: Porphyria Cutanea Tarda (PCT) — Type I (Acquired) ### Clinical Presentation This patient has the classic presentation of **porphyria cutanea tarda (PCT)**: - **Chronic photosensitivity** (not acute attacks) - **Blistering and erosions** on sun-exposed areas (dorsal hands, face, forearms) - **Hyperpigmentation and scarring** (post-inflammatory) - **Hepatic involvement** (hepatitis C is a major risk factor for Type I PCT) - **Elevated urine uroporphyrin** (predominantly Type III isomer) - **Elevated faecal porphyrins** ### Biochemical Defect **Key Point:** PCT is caused by deficiency of **uroporphyrinogen decarboxylase (UROD)**, the fifth enzyme in the heme synthesis pathway. This enzyme catalyzes the sequential decarboxylation of uroporphyrinogen to coproporphyrinogen. ### Types of PCT | Feature | Type I (Acquired) | Type II (Familial) | Type III (Familial) | | --- | --- | --- | --- | | **Inheritance** | Acquired (sporadic) | Autosomal dominant | Autosomal dominant | | **UROD activity** | ↓ in liver only | ↓ in all tissues | ↓ in all tissues | | **Family history** | No | Yes | Yes | | **Frequency** | 80% of PCT cases | 10–15% | Rare | | **Triggers** | Hepatitis C, HIV, alcohol, estrogens, iron overload | Genetic mutation | Genetic mutation | **High-Yield:** Type I PCT is the most common form and is **acquired**, often triggered by hepatitis C, HIV, or other liver disease. It is NOT inherited. ### Pathophysiology 1. **UROD deficiency** (acquired in Type I, genetic in Types II/III) 2. **Impaired conversion** of uroporphyrinogen → coproporphyrinogen 3. **Accumulation of uroporphyrin** (especially Type III isomer) 4. **Uroporphyrin is highly photosensitive** → generates reactive oxygen species (ROS) in skin upon UV exposure 5. **Photochemical damage** → blistering, erosion, scarring, hyperpigmentation ### Mechanism of Skin Damage ```mermaid flowchart TD A[UROD Deficiency]:::outcome --> B[Uroporphyrin Accumulation]:::outcome B --> C[Uroporphyrin in Skin]:::outcome C --> D{UV Exposure}:::decision D -->|Yes| E[Photochemical Excitation]:::action E --> F[ROS Generation]:::action F --> G[Collagen Damage & Inflammation]:::action G --> H[Blistering, Erosion, Scarring]:::outcome D -->|No| I[Asymptomatic]:::outcome ``` ### Risk Factors for Type I PCT - **Hepatitis C infection** (most common, 50–80% of Type I PCT) - **HIV infection** - **Alcohol abuse** - **Estrogen use** (oral contraceptives, hormone replacement) - **Iron overload** (haemochromatosis, repeated transfusions) - **Smoking** **Clinical Pearl:** Hepatitis C is the single most important risk factor for Type I PCT in developed countries. In India, hepatitis C and alcohol are major triggers. ### Laboratory Findings - **Urine porphyrins:** ↑↑ uroporphyrin (Type III > Type I) - **Faecal porphyrins:** ↑ uroporphyrin and heptacarboxyl porphyrin - **Plasma porphyrins:** May be elevated - **Liver function:** Often abnormal (hepatitis C, cirrhosis) - **Iron studies:** May show iron overload - **No acute neurovisceral symptoms** (unlike acute porphyrias) ### Management 1. **Avoid triggers:** Sun exposure (sunscreen SPF >30), alcohol, estrogens, iron supplements 2. **Treat underlying disease:** Hepatitis C (direct-acting antivirals), HIV (ART) 3. **Phlebotomy:** Reduce iron overload (target ferritin <50 ng/mL) 4. **Low-dose hydroxychloroquine:** 100–200 mg twice weekly (mobilizes uroporphyrin for urinary excretion) 5. **Symptomatic care:** Wound care, infection prevention **High-Yield:** Phlebotomy and low-dose hydroxychloroquine are the cornerstones of PCT management. Remission can be achieved with sustained treatment. ### Mnemonic for PCT Triggers: **SHAVE** - **S** — Smoking, Sun exposure - **H** — Hepatitis C, HIV - **A** — Alcohol, Antiestrogens (avoid) - **V** — Viral infections - **E** — Estrogens (oral contraceptives) ### Comparison: PCT vs. Acute Porphyrias | Feature | PCT (Cutaneous) | AIP (Acute) | Variegate Porphyria | | --- | --- | --- | --- | | **Enzyme defect** | UROD ↓ | PBGD ↓ | Protoporphyrinogen oxidase ↓ | | **Acute visceral crisis** | No | **Yes** (hallmark) | Yes | | **Photosensitivity** | **Yes** (blistering) | No | Yes (variable) | | **Urine PBG** | Normal | ↑↑↑ (acute attacks) | Normal or ↑ | | **Urine uroporphyrin** | ↑↑↑ | Normal | Normal | | **Dark urine** | Yes (chronic) | Yes (acute) | Variable | | **Inheritance** | Type I: Acquired; Types II/III: AD | AD | AD | **Key Point:** PCT is distinguished from acute porphyrias by the **absence of acute neurovisceral symptoms** and the **presence of chronic photosensitivity with blistering**.