Porphyria

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Porphyria

The porphyrias are a group of rare inherited (occasionally acquired) metabolic disorders caused by defects in the heme biosynthesis pathway. Each type reflects a specific enzyme deficiency, leading to the accumulation of toxic porphyrin intermediates upstream of the block. The name comes from the Greek for "purple," referring to the red-purple pigmentation these intermediates impart to urine. - Lippincott's Illustrated Reviews: Biochemistry, 8e

Heme Synthesis Pathway and Enzyme Defects

The diagram below maps the entire heme pathway, showing which enzyme is deficient in each type of porphyria and whether the resulting accumulation is hepatic or erythropoietic:

The key principle: defects early in the pathway (before tetrapyrrole ring formation) cause ALA and PBG accumulation, producing abdominal and neuropsychiatric symptoms. Defects later in the pathway (after ring formation) cause accumulation of photosensitizing tetrapyrrole intermediates, producing cutaneous photosensitivity. - Lippincott's Biochemistry, 8e

Classification

Porphyrias are classified by:

Site of enzyme defect: hepatic vs. erythropoietic
Clinical behavior: acute (neurovisceral attacks) vs. non-acute (cutaneous only)

Type	Enzyme Deficient	Inheritance	Major Features
ALA dehydratase deficiency porphyria (ADP)	ALA dehydratase (ALAD)	AR	Acute; very rare
Acute Intermittent Porphyria (AIP)	Hydroxymethylbilane synthase (HMBS / PBG deaminase)	AD	Acute neurovisceral; no skin
Porphyria Cutanea Tarda (PCT)	Uroporphyrinogen decarboxylase (UROD)	AD (or acquired)	Most common porphyria; skin only
Hereditary Coproporphyria (HCP)	Coproporphyrinogen oxidase (CPO)	AD	Acute + skin (mild)
Variegate Porphyria (VP)	Protoporphyrinogen oxidase (PPOX)	AD	Acute + skin (PCT-like)
Congenital Erythropoietic Porphyria (CEP)	Uroporphyrinogen III synthase	AR	Severe photosensitivity from infancy
Erythropoietic Protoporphyria (EPP)	Ferrochelatase	AD/AR	Photosensitivity; risk of liver disease
X-linked Protoporphyria (XLEPP)	ALAS2 gain-of-function	X-linked	EPP-like

Acute Hepatic Porphyrias (AIP, HCP, VP, ADP)

Pathogenesis

In the hepatic porphyrias, reduced heme synthesis removes the normal negative feedback on ALAS1. This derepresses ALAS1, driving overproduction of ALA and PBG. ALA accumulation is neurotoxic and is responsible for most of the neurologic sequelae. - Lippincott's Biochemistry, 8e

Precipitating Factors

Drugs metabolized by cytochrome P450 (e.g., barbiturates, sulfonamides, rifampicin, oral contraceptives containing progestins)
Hormonal shifts - menstrual cycle, pregnancy
Dietary restriction / fasting (reduces heme synthesis)
Infections, alcohol, stress

Clinical Presentation

Attacks typically begin with severe colicky abdominal pain, followed by:

Neuropsychiatric: agitation, hallucinations, anxiety, delirium, seizures
Motor neuropathy: ascending weakness mimicking Guillain-Barré syndrome (GBS); can be proximal or distal, asymmetric, may involve face/bulbar musculature
Autonomic: tachycardia, hypertension, pupillary dilation, constipation, urinary retention, incontinence
Hyponatremia: due to SIADH
Urine: brown or port-wine colored; darkens on exposure to light and air (ALA/PBG oxidation)

On nerve conduction studies: markedly reduced CMAP amplitudes with signs of axonal degeneration on needle EMG. CSF protein is normal or mildly elevated. - Harrison's 22e

AIP has no photosensitivity. HCP and VP add photosensitive blistering skin lesions to the neurovisceral picture.

Laboratory Diagnosis

Urine ALA and PBG: elevated during attacks (the screening test of choice)
Specific enzyme activity in erythrocytes or leukocytes
Stool porphyrins: elevated fecal coproporphyrins in HCP and VP
VP has a characteristic plasma fluorescence at 626 nm; HCP at 619 nm

Treatment of Acute Attacks

Remove precipitants - stop offending drugs, treat infections
IV glucose 10-20 g/h - reduces ALAS1 induction; adequate for mild attacks
IV hemin (hematin) 2-5 mg/kg/day for 3-14 days - replenishes heme, suppresses ALAS1; used if no improvement within 24 h
Givosiran (Givlaari) - a subcutaneous siRNA that silences hepatic ALAS1 mRNA; 2.5 mg/kg monthly; shown in clinical trials to reduce attack frequency, lower urinary ALA/PBG, improve pain scores and quality of life; approved for recurrent acute intermittent porphyria - Harrison's 22e
Supportive: opioids for pain, beta-blockers for autonomic instability, benzodiazepines for seizures

Porphyria Cutanea Tarda (PCT) - Most Common

PCT is the most common porphyria, caused by deficiency of uroporphyrinogen decarboxylase (UROD) in the liver. Only ~20% have germline UROD mutations (Type II); the remainder have acquired enzymatic inhibition by iron-generated oxidants in the liver (Type I). - Lippincott's Biochemistry, 8e

Risk/triggering factors: hepatic iron overload, excess alcohol, estrogen therapy, hepatitis B or C, HIV infection, hemochromatosis (HFE mutations), halogenated hydrocarbons.

Clinical features (onset typically 4th-5th decade):

Blisters, erosions, and crusts on sun-exposed areas (dorsal hands most common)
Skin fragility
Hypertrichosis (face, temporal area)
Hyperpigmentation and milia
Scleroderma-like changes

Skin eruptions (blisters, erosions, crusts) on the dorsal hands of a patient with porphyria cutanea tarda

Biochemistry: urine uroporphyrin markedly elevated (>uroporphyrin I predominates); normal urine PBG distinguishes PCT from acute porphyrias.

Treatment:

Eliminate triggers (stop alcohol, estrogen, iron supplements)
Phlebotomy (450 mL every 2 weeks) to reduce hepatic iron overload - allows new UROD to be synthesized
Low-dose hydroxychloroquine (100-200 mg twice weekly) - equally effective to phlebotomy; chelates and mobilizes uroporphyrins from liver; used when phlebotomy is contraindicated (e.g., anemia)
Treat underlying hepatitis C - Yamada's Gastroenterology, 7e; Fitzpatrick's Dermatology

Variegate Porphyria (VP)

VP combines features of both PCT and AIP - it is also known as "South African genetic porphyria" because of a founder mutation (R59W in PPOX) highly prevalent in Afrikaner populations. The deficient enzyme is protoporphyrinogen oxidase (PPOX). - Andrews' Diseases of the Skin

40-70% have skin symptoms (PCT-like blistering)
27% have acute neurovisceral attacks
14% have both simultaneously
Key diagnostic finding: plasma fluorescence at 626 nm (unique to VP)
Fecal coproporphyrins and protoporphyrins are always elevated
Urinary coproporphyrin > uroporphyrin (distinguishes from PCT)

VP patients (like HCP and AIP patients) have an increased long-term risk of hepatocellular carcinoma - liver imaging is recommended after age 50. - Andrews' Diseases of the Skin

Erythropoietic Porphyrias

Congenital Erythropoietic Porphyria (CEP - Günther's disease)

AR deficiency of uroporphyrinogen III synthase
Most severe porphyria; presents in infancy with dark urine and photosensitivity
Uroporphyrinogen I and coproporphyrinogen I accumulate (isomer I has no physiological role)
Features: vesicles/bullae on sun-exposed skin, sclerodermoid scarring, hypertrichosis, red fluorescent teeth (erythrodontia), hemolytic anemia
Treatment: strict sun protection, blood transfusions; bone marrow transplantation may be curative

Erythropoietic Protoporphyria (EPP)

Deficiency of ferrochelatase (AD with reduced penetrance, or AR)
Protoporphyrin accumulates in erythrocytes, bone marrow, and plasma
Presents in early childhood with acute painful photosensitivity (burning, itching within minutes of sun exposure) - no blistering
Risk of cholestatic liver disease from protoporphyrin accumulation
β-carotene (provitamin A) and afamelanotide (an alpha-MSH analog) are used for photoprotection

Hepatoerythropoietic Porphyria (HEP)

HEP is the homozygous form of PCT (homozygous or compound heterozygous UROD deficiency, with activity ~10% of normal). Clinical features resemble CEP but are distinguished biochemically by elevated erythrocyte protoporphyrins + urinary uroporphyrins. - Andrews' Diseases of the Skin

Pseudoporphyria

Not a true porphyria. Patients develop PCT-like blistering with normal porphyrin levels. Caused by NSAIDs (especially naproxen), voriconazole, tetracyclines, imatinib, tanning beds, and hemodialysis. Treatment: discontinue the offending agent and sun protection. - Andrews' Diseases of the Skin

Key Distinguishing Points (Summary)

Feature	AIP	PCT	VP	HCP	EPP
Neurovisceral attacks	Yes	No	Yes	Yes	No
Photosensitivity/skin	No	Yes	Yes	Mild	Yes (acute burning)
Urine PBG elevated	During attacks	Normal	During attacks	During attacks	Normal
Key diagnostic test	Urine ALA/PBG	Urine uroporphyrin	Plasma fluor. 626 nm	Fecal coproporphyrin	Erythrocyte protoporphyrin
Inheritance	AD	AD/acquired	AD	AD	AD/AR

Recent Evidence (PubMed 2024-2026)

A 2024 meta-analysis on acute hepatic porphyria and hepatocellular carcinoma (PMID 39438413) confirmed that patients with acute hepatic porphyria have a significantly elevated risk of HCC, supporting current recommendations for regular liver surveillance after age 50 in all acute porphyria patients.

Sources: Harrison's Principles of Internal Medicine 22e; Lippincott's Illustrated Reviews: Biochemistry 8e; Andrews' Diseases of the Skin; Fitzpatrick's Dermatology; Yamada's Textbook of Gastroenterology 7e; Bradley and Daroff's Neurology in Clinical Practice

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