Porphyria

BASICS

Porphyria describes a variety of disorders of heme biosynthesis.

Description

• Heme: Primarily synthesized in erythropoietic cells for hemoglobin synthesis and liver parenchymal cells for cytochrome and hemoprotein synthesis (1):
  • Liver rate-limiting step: 5-aminolevulinic acid synthase (ALAS)
  • Erythroid cell rate limiting step: Iron availability
• Porphyria: Inherited and acquired metabolic disorders due to defect in heme biosynthesis leading to accumulation and excessive excretion of porphyrins (2):
  • 8 enzymes involved in synthesis of heme: Defect at any step leads to porphyria
  • Complete enzyme deficiencies incompatible with life
• Classification:
  • Acute vs. chronic porphyrias (2,3)
  • Acute: AIP, HCP, VP, ALAD-P
  • Chronic: PCT, HEP, EPP, CEP
• System(s) affected: Gastrointestinal; Skin/Exocrine; Hematologic/Lymphatic/Immunologic; Nervous
• Acute porphyrias:
  • Acute intermittent porphyria (AIP) (2):
    • Inheritance: Autosomal dominant
    • Classification: Acute
    • Deficiency of porphobilinogen deaminase
    • Symptoms: Purely neurologic (question whether ALA or PBG is neurotoxic)
  • Hereditary coproporphyria (HCP) (2):
    • Inheritance: Autosomal dominant
    • Classification: Acute
    • Deficiency of coproporphyrinogen oxidase
    • Symptoms: Neurovisceral, dermatologic (5%)
  • Variegate porphyria (VP) (2):
    • Inheritance: Autosomal dominant
    • Classification: Acute
    • Deficiency of protoporphyrinogen oxidase
    • Symptoms: Neurologic and dermatologic (60%) (1):
      • Dermatologic symptoms do not respond to phlebotomy or chloroquine.
      • Acute attacks peak in 20s; more common in women
    • Specific labs: Plasma fluorescence emission spectroscopy peak at 624–628 nm distinguishes VP from AIP and HCP (both have peaks at 620 nm).
  • δ-Aminolevulinate dehydratase deficiency porphyria (ALAD-P) (2):
    • Rarest form of porphyria
    • Inheritance: Autosomal recessive
    • Classification: Acute
    • Deficiency of δ-aminolevulinic acid dehydratase (ALAD) causing unopposed ALAS expression in liver:
      • Acute attack due to overexpression of ALA synthetase (ALAS) in liver due to lack of negative feedback from deficient ALAD
      • Partial deficiency does not produce clinical symptoms.
    • Specific labs: Urinary coproporphyrin III and erythrocyte zinc-protoporphyrin
• Chronic porphyrias:
  • Porphyria cutanea tarda (PCT) (1,2):
    • Most common and readily treated porphyria, indistinguishable from VP
    • Inheritance: Autosomal dominant in 20% (type II, expressed in all tissues), may be acquired mutation (type I; expressed only in the liver)
    • Classification: Chronic
    • Deficiency of uroporphyrinogen decarboxylase
    • Symptoms: Dermatologic: Blood vessels of papillary dermis site of injury:
      • Skin fragility: Negligible trauma causes superficial erosion that eventually forms crust; secondary infection common
      • Hypertrichosis
      • Increased pigmentation
    • Specific labs: Plasma fluorescent spectrum to differentiate VP and PCT
    • Specific treatment:
      • Phlebotomy for 3–6 months (this is the treatment of choice in patients with hemochromatosis)
      • Chloroquine (low dose) over 6–12 months only if no hemochromatosis
• Erythropoietic protoporphyria (EPP) (1,2):
  • Inheritance: Autosomal dominant vs. co-inheritance
  • Deficiency of mitochondrial ferrochelatase
  • Classification: Chronic
  • Symptoms: Dermatologic, GI:
    • Dermatologic: Transient skin redness, swelling, pruritus, burning after sunlight exposure
    • GI: Liver dysfunction, gallstones, cholestatic liver failure due to accumulation of protoporphyrin
  • Specific labs: High protoporphyrin in RBCs, bone marrow, and plasma
  • Specific treatment:
    • Skin burning: Apply cold water
    • Afamelanotide: α-melanocyte-stimulating hormone analogue to induce photoprotective epidermal melanin formation
    • Oral β-carotene if nonsmoker
    • Cholestyramine or activated charcoal for liver dysfunction
    • Transplantation for liver failure
• Congenital erythropoietic porphyria (CEP) (1,2):
  • Rare and panethnic
  • Inheritance: Autosomal recessive
  • Classification: Chronic
  • Deficiency of uroporphyrinogen III cosynthase
  • Symptoms:
    • Dermatologic: Photosensitivity
    • Ocular: Chronic ulcerative keratitis, corneal scarring
  • Specific treatment:
    • Photoprotection: Change day-night rhythm
    • Splenectomy (reduces hemolysis and platelet consumption)
    • Bone marrow transplantation
• Hepatoerythropoietic porphyria (HEP) (1,2,3):
  • Inheritance: Autosomal recessive
  • Classification: Chronic
  • Deficiency of uroporphyrinogen decarboxylase
  • Symptoms: Presents in infancy or childhood with red urine, blistering, skin lesions, hypertrichosis, and scarring
  • Specific treatment: Phlebotomy and chloroquine not effective; primary treatment is photoprotection (avoid sunlight)

Epidemiology

• Gender prevalence: Female > Male (3)
• AIP (4):
  • Incidence: 1 per 100,000
  • Onset: 20–40 years old, rarely before puberty
• VP (4):
  • Incidence: 1 per 300 in South Africa, rare elsewhere
  • Onset: 20–30 years, rare before puberty
• HCP (4):
  • Incidence: <50 total cases
  • Onset: Rare before puberty
• ALAD-P (4):
  • Incidence: <10 total cases
  • Onset: Bimodal in early and late years
• PCT (4):
  • Incidence: Most common porphyria worldwide
  • Onset: 30–40 years, rare before puberty
• EPP (4):
  • Incidence: 2nd most common of cutaneous porphyrias
  • Onset: 1–4 years, rare later in life
• CEP (4):
  • Incidence: ~150 total cases
  • Onset: Infancy to 1st decade of life
• HEP (4):
  • Incidence: ~25 total cases
  • Onset: Early infancy

Prevalence

• More common in whites than in Asians or individuals of African descent
• PCT: 1/10,000; most common of the porphyrias in the US and Europe
• AIP, HCP, VP: 1/10,000–1/100,000. The prevalence in Europe is ∼1/75,000. In northern Sweden, because of a founder effect, the estimated prevalence is 1/1,000 (1).

Risk Factors

• Acute porphyria triggers (AIP, HCP, VP, ALAD-P) (3):
  • Viral infections
  • Hypocaloric diet
  • Alcohol
  • Drugs (e.g., barbiturates, sulfa)
  • Stress
  • Steroid hormones
  • Pregnancy
• Hexachlorobenzene exposure

Genetics

See within descriptions of each porphyria above.

DIAGNOSIS

Physical Exam

Symptoms of acute attacks (1):

• Duration: 1–2 weeks
• Mortality up to 10%
• Prodromic phase with behavioral changes (anxiety, restlessness, insomnia)
• GI: Abdominal pain, nausea, vomiting, constipation
• Psychiatric: Anxiety, depression, disorientation, hallucination, paranoia, confusion seen in 20–30%
• Cardiac: Tachycardia, hyperhidrosis, hypertension
• Imaging: Abdominal x-ray normal or with mild bowel ileus
• Labs: Dehydration, hyponatremia due to inappropriate antidiuretic hormone secretion in 40%, electrolyte imbalance
• Neurologic: Seizures due to hyponatremia or hypomagnesemia, neuropathy (mostly motor), normal CSF
• Urine: Excretion red or dark-colored urine

Tests

• Urinary porphobilinogen, porphyrins, 5-aminolevulinic acid
• Genetic studies when applicable

Lab

• Gold standard: DNA analysis to identify causative mutation (3):
  • ALAD-P: ALAD, chromosome 9q34
  • AIP: HMBS, chromosome 11q24
  • VP: PPOX, chromosome 3q19
  • HCP: CPOX, chromosome 1q22–23
  • CEP: UROS, chromosome 10q25.2
  • PCT: UROD, chromosome 1p34
  • EPP: FECH, chromosome 18q21.3
  • HEP: UROD, chromosome 1p34
• Urine: Assess for excess alanine (ALA) and porphobilinogen (1,3):
  • Acute attack confirmed by excretion >10× upper limit
• Serum: ALA levels to differentiate from other causes of abdominal pain (1,3)
• Plasma fluorescence emission spectroscopy (3)

Differential Diagnosis

• The differential diagnosis includes a spectrum of neurologic, psychiatric, and dermatologic disorders.
• Pseudoporphyria is a rare syndrome—indistinguishable from porphyria cutanea tarda—caused by some NSAIDs (e.g., nabumetone and naproxen) and flutamide.

TREATMENT

Medication (Drugs)

First Line

Acute porphyrias:

• Preventive: Avoid sun exposure, precipitating drugs, alcohol, smoking, cannabis, dieting, fasting (1):
  • List of safe and unsafe drugs at www.drugs-porphyria.org (3)
• First-line treatment (1):
  • IV heme:
    • Monitor urinary porphobilinogen excretion to document response.
    • Administer with 1:1 dilution in 4–20% human serum albumin to increase solubility, stability, and lower risk of vein injury.
    • Can be used during pregnancy
    • Monitor for iron overload using iron studies.
  • Monitor fluids and electrolytes:
    • Avoid hyponatremia.
    • Maintain caloric intake with PO carbohydrate-rich food supplements or IV normal saline with 5% dextrose.

• Supportive treatment (1):
  • Abdominal pain: Opiates, aspirin
  • Vomiting: Antiemetics
  • Constipation: Laxatives
  • Hypertension and tachycardia: β-Blockers
  • Neuropathy: Opiates, physiotherapy
  • Adrenergic symptoms: IV magnesium sulfate

• Chronic porphyrias: Specific treatments listed in the “Description” section.

Additional Treatment

General Measures

• Neuropsychiatric–abdominal: Avoid precipitating drugs, alcohol, known toxins.
• Dermatologic: Shade, protective clothing, avoid skin trauma; for porphyria cutanea tarda, weekly or monthly phlebotomy may help to prevent attacks.
• Congenital erythropoietic porphyria: Consider bone marrow transplant.

Ongoing Care

Diet

Neuropsychiatric: Anecdotal evidence carbohydrates help to reduce symptoms or frequency of attacks

Patient Education

• The American Porphyria Foundation, P.O. Box 22712, Houston, TX 77227; 713-266-9617 or 1-866-APF-3635 (toll-free); fax: 713-840-9552; www.porphyriafoundation.com/
• The Drug Database for Acute Porphyria: www.drugs-porphyria.org/
• European Porphyria Network: www.porphyria-europe.com/

Prognosis

• In all porphyrias:
  • Asymptomatic or minimally symptomatic: Unaffected longevity
  • Neurologic complications (e.g., peripheral neuropathy, neurosis, or hemiplegia) may be permanent.
• In AIP:
  • Acute attacks have 25% mortality.
  • Increased risk of hepatocellular carcinoma
• <10% of patients develop recurrent acute attacks (1).

Porphyria Cutanea Tarda: 

Porphyria cutanea tarda (PCT) is a condition resulting from a defect in the heme biosynthesis pathway—reduced activity of the hepatic uroporphyrinogen decarboxylase (UROD) enzyme, which is the 5th enzyme in the heme biosynthetic pathway. This causes buildup of uroporphyrinogens in blood and urine. The buildup of porphyrins in the blood causes skin manifestations.

Image (induced by Tomoxifen)