A 35-year-old man of Gujarati descent presents with a 2-year history of progressive photosensitivity, blistering lesions on the dorsal surfaces of hands and forearms, and hyperpigmentation of sun-exposed areas. He also reports dark urine and mild hepatomegaly on examination. Liver function tests show elevated transaminases (AST 85 U/L, ALT 92 U/L) and mild elevation of GGT. Serum ferritin is elevated at 420 ng/mL. Urine analysis shows elevated uroporphyrin (>1000 μmol/24 h) and coproporphyrin. Fecal porphyrins are normal. Plasma porphyrins are normal. Which of the following is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Porphyria Cutanea Tarda (PCT) ### Key Clinical Features Matching This Case **Key Point:** PCT is the most common porphyria and presents with: 1. **Chronic photosensitive skin lesions** — bullae, erosions, and scarring on sun-exposed areas (dorsal hands, forearms, face) 2. **Hyperpigmentation** — increased melanin deposition in affected areas 3. **Hepatic involvement** — elevated transaminases, hepatomegaly, cirrhosis risk 4. **Dark urine** — due to elevated urinary porphyrins 5. **NO acute neurovisceral symptoms** — distinguishes it from acute porphyrias ### Pathophysiology **High-Yield:** PCT results from deficiency of **uroporphyrinogen decarboxylase (UROD)**, the fifth enzyme in heme synthesis. Two types exist: | Feature | Type I (80%) | Type II (20%) | |---------|--------------|---------------| | **Inheritance** | Sporadic (acquired) | Autosomal dominant | | **UROD deficiency** | Liver only | Liver + RBCs | | **Family history** | Absent | Often present | | **Triggers** | Alcohol, estrogens, hepatitis C, HIV, iron overload | Same as Type I | | **Prognosis** | Can remit with treatment | Persistent | ### Why This Patient Has PCT **Clinical Pearl:** The diagnostic triad for PCT is: 1. **Markedly elevated urine uroporphyrin** (>1000 μmol/24 h) — pathognomonic 2. **Elevated urine coproporphyrin** (but less than uroporphyrin) 3. **Normal or low fecal porphyrins** — key distinguishing feature **Mnemonic: PCT = Porphyria Cutanea Tarda** - **P**hotosensitivity (chronic, not acute) - **C**utaneous lesions (bullae, fragility, scarring) - **T**arda (late-onset, gradual progression) - **U**roporphyrin elevated in urine (>1000 μmol/24 h) - **R**ed urine (porphyrin oxidation) - **A**cquired in 80% (Type I, sporadic) - **T**riggers: alcohol, estrogens, hepatitis C, iron - **A**ssociated with liver disease - **R**UROD deficiency (uroporphyrinogen decarboxylase) - **D**ark urine, NOT dark during acute attack - **A**bsent acute neurovisceral symptoms ### Diagnostic Confirmation ```mermaid flowchart TD A[Chronic photosensitive skin lesions]:::outcome --> B[Measure urine porphyrins]:::action B --> C{Uroporphyrin pattern?}:::decision C -->|Markedly elevated uroporphyrin<br/>Elevated coproporphyrin<br/>Normal fecal porphyrins| D[Porphyria Cutanea Tarda]:::outcome C -->|Elevated coproporphyrin<br/>Elevated fecal coproporphyrin| E[Hereditary Coproporphyria]:::outcome C -->|Elevated protoporphyrin<br/>Elevated fecal protoporphyrin| F[Variegate Porphyria]:::outcome A --> G[Check liver function]:::action G --> H[Elevated transaminases<br/>Hepatomegaly<br/>Cirrhosis risk]:::outcome ``` ### Associated Conditions in PCT **High-Yield:** PCT is strongly associated with: - **Hepatitis C virus (HCV)** — 50–80% of patients in endemic areas - **HIV infection** — increased risk - **Alcohol abuse** — common trigger - **Estrogen use** — oral contraceptives, HRT - **Iron overload** — hemochromatosis, multiple transfusions - **Liver cirrhosis** — end-stage complication This patient's elevated ferritin suggests iron overload as a contributing factor. ### Management of PCT **Clinical Pearl:** Treatment aims to reduce hepatic porphyrin production: 1. **Phlebotomy** — first-line for iron overload (target ferritin <100 ng/mL) 2. **Low-dose chloroquine** — mobilizes hepatic porphyrins (200 mg twice weekly) 3. **Avoid triggers** — stop alcohol, estrogens, iron supplements 4. **Screen for HCV, HIV** — treat if present 5. **Sun protection** — topical sunscreen, protective clothing ### Why NOT the Other Options **Acute intermittent porphyria:** - Presents with **acute neurovisceral crises** (severe abdominal pain, constipation, neuropsychiatric symptoms) — NOT chronic skin lesions - Urine shows elevated ALA and PBG, NOT uroporphyrin - NO photosensitivity or skin blistering **Variegate porphyria:** - Presents with **both acute neurovisceral attacks AND photosensitive skin lesions** - **Elevated fecal porphyrins** (coproporphyrin and protoporphyrin) — distinguishes it from PCT - Urine shows elevated coproporphyrin and protoporphyrin, NOT predominantly uroporphyrin - Plasma porphyrins are elevated (unlike PCT where they are normal) **Hereditary coproporphyria:** - Can cause **acute neurovisceral attacks** (like AIP) — this patient has NO acute symptoms - **Elevated fecal coproporphyrin** — this patient's fecal porphyrins are normal - Urine shows elevated coproporphyrin, but NOT the marked uroporphyrin elevation seen here - Plasma porphyrins are elevated **Table: Differential Diagnosis of Porphyrias** | Feature | PCT | AIP | Variegate | Hereditary Copro | |---------|-----|-----|-----------|------------------| | **Acute attacks** | No | Yes | Yes | Yes | | **Photosensitivity** | Yes (chronic) | No | Yes | No | | **Urine uroporphyrin** | ↑↑↑ | Normal | ↑ | Normal | | **Urine ALA/PBG** | Normal | ↑↑↑ | Normal | ↑ | | **Fecal porphyrins** | Normal | Normal | ↑↑↑ | ↑↑↑ | | **Plasma porphyrins** | Normal | Normal | ↑ | ↑ | | **Enzyme defect** | UROD | PBGD | PROTO | COPRO | [cite:Harrison 21e Ch 298; Robbins 10e Ch 7]