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Summary Table

Category	Detail
Risk Factors	Hepatitis C infection, chronic alcohol use, estrogen therapy (OCPs, HRT), HIV, hereditary hemochromatosis (HFE gene mutations), smoking, dialysis patients
Etiology	Deficiency of uroporphyrinogen decarboxylase (UROD) in the liver, leading to accumulation of porphyrins in the skin
Patient Presentation	Painless blistering on sun-exposed skin (dorsal hands, forearms, face), skin fragility, and chronic photosensitivity; patients often report that minor trauma causes blisters and erosions
Classic Physical Exam	Vesicles and bullae on dorsal hands, hypertrichosis (excess facial hair, particularly in women), hyperpigmentation, scarring/milia at healed blister sites, sclerodermoid plaques in advanced cases
Key Diagnostic Results	Elevated urine uroporphyrins (with a high uroporphyrin-to-coproporphyrin ratio), plasma porphyrin fluorescence at ~618 nm (pink-red fluorescence under Wood lamp), elevated serum ferritin and transferrin saturation
Management	Phlebotomy (first-line to reduce hepatic iron), low-dose hydroxychloroquine as an alternative, avoidance of triggers (alcohol, estrogen, iron supplementation)
Keywords	"Blisters on dorsal hands," "tea-colored urine," "skin fragility in sun-exposed areas," "hypertrichosis," "hepatitis C association," "elevated uroporphyrins"

1. Pathophysiology

PCT is the most common porphyria and results from decreased activity of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme biosynthesis pathway. UROD converts uroporphyrinogen to coproporphyrinogen in the liver. When this enzyme is inhibited, uroporphyrinogen and other highly carboxylated porphyrinogens accumulate in hepatocytes and eventually spill into the bloodstream.

The critical concept here is that these accumulated porphyrins are photoactive molecules. Once deposited in the skin, they absorb ultraviolet light (particularly in the Soret band near 400 nm) and generate reactive oxygen species through a type II photochemical reaction. This oxidative damage targets the dermal-epidermal junction, degrading anchoring structures such as type IV collagen and laminin. This is why the blisters form in a subepidermal plane and why the skin becomes mechanically fragile even with minor shear forces.

There are two forms to understand. Sporadic (Type I) accounts for roughly 80% of cases and involves no inherited UROD mutation; instead, the enzyme is inhibited by hepatic iron overload and oxidative stress from triggers such as alcohol, hepatitis C, estrogen, or HIV. Familial (Type II) involves an autosomal dominant mutation in the UROD gene that reduces baseline enzyme activity to about 50%, but clinical disease still requires an additional environmental trigger to push enzyme function below the critical threshold of approximately 20%.

The reason iron plays such a central role is that excess hepatic iron catalyzes the oxidation of uroporphyrinogen to uroporphomethene, which acts as a direct competitive inhibitor of UROD. This creates a vicious cycle: more iron leads to more porphyrin accumulation, more oxidative damage, and further enzyme inactivation. This is why nearly all PCT patients have some degree of elevated ferritin and transferrin saturation, and why iron reduction through phlebotomy is the cornerstone of treatment.

The liver involvement also explains why PCT is associated with elevated transaminases and why long-standing PCT carries a risk of hepatocellular carcinoma, independent of any concurrent hepatitis C.

2. Classification and Clinical Manifestation

Type	Mechanism	Inheritance	Enzyme Activity	Clinical Notes
Type I (Sporadic)	Acquired inhibition of hepatic UROD	None	Reduced only in the liver	~80% of cases; triggered by alcohol, HCV, estrogen, iron overload; no family history
Type II (Familial)	Heterozygous UROD gene mutation	Autosomal dominant	~50% in all tissues	Clinically indistinguishable from Type I but presents earlier in life; still requires a trigger
Type III (Familial, gene-negative)	Unknown genetic defect (not UROD mutation)	Familial clustering	Reduced only in the liver	Rare; behaves like Type I but runs in families without identifiable UROD mutations
Hepatoerythropoietic Porphyria (HEP)	Homozygous or compound heterozygous UROD mutation	Autosomal recessive	<10% in all tissues	Presents in childhood with severe photosensitivity, resembles congenital erythropoietic porphyria; very rare

By Stage

Stage	Findings
Early	Skin fragility, easy blistering on dorsal hands and forearms after sun exposure or minor trauma
Established	Tense vesicles and bullae that rupture easily, leaving erosions that heal slowly with crusting
Chronic/Healed	Milia (small white cysts in areas of healed blisters), scarring, dyspigmentation (both hyper- and hypopigmentation)
Advanced	Hypertrichosis (face and arms), sclerodermoid thickening (waxy induration resembling morphea), dystrophic calcification

3. Diagnostic Workup

Test	Role	Expected Finding
Urine porphyrins (24-hour or spot)	Best initial test	Elevated total porphyrins with predominance of uroporphyrins; uroporphyrin-to-coproporphyrin ratio >3:1
Plasma porphyrin fluorescence emission spectroscopy	Confirmatory / most accurate test	Characteristic emission peak at ~618 nm (distinguishes PCT from other porphyrias like variegate porphyria, which peaks at ~626 nm)
Wood lamp examination of urine	Bedside screening	Coral-pink or orange-red fluorescence of urine under long-wave UV
Serum ferritin and transferrin saturation	Assess iron status	Typically elevated; supports the diagnosis and guides phlebotomy
Hepatitis C serology	Mandatory screening	Positive in a large proportion of sporadic PCT cases
HIV testing	Screening	PCT can be the presenting sign of HIV
HFE gene mutation analysis	Evaluate for hereditary hemochromatosis	C282Y or H63D mutations increase susceptibility
Liver function tests	Assess hepatic involvement	Often mildly elevated ALT/AST
Skin biopsy	When diagnosis is uncertain	Subepidermal blister with minimal inflammation, PAS-positive thickening of dermal vessel walls ("caterpillar bodies" representing degenerated keratinocytes along the roof of the blister)

The best initial test when you suspect PCT is a urine porphyrin profile. The hallmark is a dramatic elevation of uroporphyrins (often 10 to 50 times normal) with a high uroporphyrin-to-coproporphyrin ratio. This pattern is fairly distinctive and separates PCT from other cutaneous porphyrias. Stool porphyrins will show elevated isocoproporphyrins, which is a finding unique to PCT and helps distinguish it from variegate porphyria.

The most accurate test is plasma porphyrin fluorescence emission spectroscopy. This is particularly important because variegate porphyria (VP) and hereditary coproporphyria (HCP) can occasionally mimic the cutaneous findings of PCT. The plasma emission peak at ~618 nm in PCT versus ~626 nm in VP is the definitive discriminator.

Once the diagnosis is established, you must screen for underlying triggers. Hepatitis C testing is considered mandatory in every new PCT diagnosis because the association is strong, and treating HCV often leads to remission of PCT. Similarly, check HIV status, iron studies (ferritin and transferrin saturation), and HFE mutations to identify concurrent hemochromatosis.

A skin biopsy is not routinely needed when the clinical picture and urine porphyrins are clear, but when performed, the subepidermal blistering pattern with festooning of dermal papillae and PAS-positive vessel wall thickening is characteristic.

4. Management and Treatment

Intervention	Details	Notes
Trigger avoidance	Discontinue alcohol, estrogen, iron supplements; sun protection with opaque physical barriers (zinc oxide sunscreen, clothing)	Chemical sunscreens that only block UVB are inadequate because porphyrin activation occurs in the visible light/UVA range
Phlebotomy (first-line)	Remove 450-500 mL of blood every 1-2 weeks until serum ferritin reaches the low-normal range (~20 ng/mL)	Typically requires 6-10 sessions over several months; clinical remission usually follows within months of achieving target ferritin
Low-dose hydroxychloroquine (alternative)	100 mg twice weekly (NOT the standard 200 mg twice daily dose used for rheumatic diseases)	Used when phlebotomy is contraindicated (anemia, poor venous access); works by forming water-soluble complexes with porphyrins, enhancing urinary excretion
Low-dose chloroquine	125 mg twice weekly	Same mechanism as hydroxychloroquine; either agent is acceptable
Treat underlying HCV	Direct-acting antiviral therapy	Successful HCV eradication often leads to PCT remission independently
Iron chelation (deferoxamine)	Rarely used	Reserved for patients who cannot undergo phlebotomy and do not tolerate antimalarials

The first action in every PCT patient is trigger elimination. Stop alcohol, discontinue estrogen-containing medications, and avoid unnecessary iron supplementation. Counsel patients on strict photoprotection, emphasizing that standard UVB-blocking sunscreens are not sufficient. Porphyrins absorb light in the Soret band (~400 nm) and into the visible spectrum, so patients need physical blocking agents (zinc oxide, titanium dioxide) or opaque clothing.

The definitive treatment is serial phlebotomy, which works by depleting hepatic iron stores. The mechanism connects directly to the pathophysiology: removing iron breaks the cycle of UROD inhibition. Each session removes approximately 450-500 mL of whole blood. Sessions are performed every 1-2 weeks, and the target endpoint is a serum ferritin in the low-normal range (approximately 20 ng/mL). Most patients require 6-10 sessions. Clinical improvement lags behind biochemical improvement; blistering typically resolves within several months after target ferritin is reached, but complete skin healing (scarring, milia) may take longer.

When phlebotomy is contraindicated (for example, in patients with concurrent anemia or those on hemodialysis with baseline low hemoglobin), low-dose antimalarials are the alternative. The critical point here is the dose: hydroxychloroquine at 100 mg twice per week or chloroquine at 125 mg twice per week. Using standard rheumatologic doses will cause a hepatotoxic porphyrin release reaction with a dramatic spike in transaminases and worsening symptoms. The low dose mobilizes porphyrins gradually, allowing renal excretion without overwhelming the liver.

If hepatitis C is identified, initiating direct-acting antiviral therapy is a priority. HCV eradication alone can produce sustained PCT remission in many patients, and treatment should not be deferred.

Monitor response with serial urine porphyrin levels and serum ferritin. Relapse can occur if triggers are reintroduced, so long-term lifestyle modification and periodic monitoring are essential.

5. Differential Diagnosis and Distractors

Diagnosis	Why It Is Similar	Key Discriminator
Variegate Porphyria (VP)	Also causes blistering on sun-exposed skin with similar vesicles and skin fragility	VP also causes acute neurovisceral attacks (abdominal pain, neuropathy, psychiatric symptoms); elevated stool protoporphyrin and a plasma fluorescence peak at ~626 nm (not 618 nm); urine ALA and PBG elevated during attacks
Hereditary Coproporphyria (HCP)	Photosensitive blistering can occur; shares features of cutaneous porphyria	HCP also presents with acute attacks; urine and stool coproporphyrins are predominantly elevated rather than uroporphyrins
Pseudoporphyria	Clinically identical skin findings (blisters, fragility, scarring on dorsal hands)	No porphyrin elevation on any testing; associated with NSAIDs (especially naproxen), tanning beds, and chronic kidney disease/dialysis
Epidermolysis Bullosa Acquisita (EBA)	Mechanobullous disease with blisters on trauma-prone sites, heals with scarring and milia	Porphyrin levels normal; direct immunofluorescence shows linear IgG at the dermal-epidermal junction; not photosensitive
Bullous Pemphigoid	Tense bullae on the skin	Lesions are pruritic and not limited to sun-exposed areas; no skin fragility or milia; linear IgG and C3 along the basement membrane zone on immunofluorescence
Dermatitis Herpetiformis	Vesicular skin lesions	Intensely pruritic grouped vesicles on extensor surfaces; associated with celiac disease, not photodistributed; granular IgA on immunofluorescence

6. Traps and High-Yield Pearls

The most common way students lose points on PCT questions is by confusing it with variegate porphyria. Both cause photosensitive blistering on dorsal hands, and both show elevated urine porphyrins. The critical discriminator is that VP also causes acute neurovisceral attacks (severe abdominal pain, peripheral neuropathy, neuropsychiatric symptoms), while PCT is purely cutaneous and never causes acute attacks. If the vignette describes blistering skin plus abdominal pain and confusion, think VP or HCP, not PCT.

The second major trap is pseudoporphyria. Test-writers love this because the clinical presentation is indistinguishable from PCT. The patient has the same blisters, the same distribution, the same scarring. The vignette will include a clue pointing to a causative drug (naproxen is the classic culprit) or chronic dialysis, and the porphyrin levels will be explicitly stated as normal. If porphyrins are normal, it cannot be PCT regardless of how classic the skin looks.

Another tested concept is the antimalarial dosing trap. Students who know that hydroxychloroquine treats PCT sometimes select the standard dose (200 mg twice daily). The correct answer is the low dose (100 mg twice per week). Standard doses cause a dangerous hepatotoxic flare.

Finally, remember the mandatory HCV screening. A question may present a patient newly diagnosed with PCT and ask for the next best step. If phlebotomy is not among the choices but hepatitis C testing is, that is the answer. The association between PCT and HCV is so strong that screening is considered part of the diagnostic workup, not an optional add-on.

The core competency being tested across PCT questions is your ability to (1) recognize the characteristic cutaneous presentation on sun-exposed areas with the correct trigger profile, (2) distinguish PCT from other blistering and porphyria conditions using the right laboratory test, and (3) apply the correct treatment at the correct dose while addressing the underlying trigger.

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