What are the diagnostic steps and treatment options for investigating porphyria?

Diagnostic Steps and Treatment Options for Porphyria

The definitive diagnosis of porphyria requires biochemical confirmation with specific tests before proceeding to genetic testing, as genetic testing alone can lead to false diagnoses and potentially harmful treatment decisions. 1

Initial Diagnostic Approach

First-Line Testing Based on Clinical Presentation

• For suspected acute neurovisceral porphyria (abdominal pain, neurological symptoms):

  • Collect a random urine sample for quantitative measurement of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) 1
  • Protect all samples from light by covering collection tubes with aluminum foil 1
  • Use morning or spot urine samples normalized to creatinine excretion (avoid 24-hour collections) 1

• For suspected cutaneous porphyria (skin photosensitivity, blistering):

  • Collect EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy 2
  • Collect whole blood for porphyrin analysis (essential for diagnosing protoporphyria) 2
  • Collect random urine sample for total urinary porphyrins (TUP) 2

Pre-analytical Requirements

• Porphyrins are light-sensitive - all samples must be protected from light 1
• PBG starts to decrease within 24 hours at room temperature - refrigerate or freeze samples 1
• Urine samples with creatinine below 2 mmol/L may give falsely elevated results 1, 2

Diagnostic Algorithm for Acute Porphyrias

1. Initial screening:

   • Measure urinary PBG and ALA during symptomatic episodes 1, 3
   • Normal PBG/ALA levels during symptoms effectively rule out acute porphyria 1
   • Significantly elevated PBG (>10× upper limit of normal) confirms acute porphyria attack 1

2. Differential diagnosis between acute porphyria types:

   • Further analysis of urine, plasma, and fecal porphyrins to identify specific type (AIP, VP, HCP, or ALAD) 2
   • Consider that ALA can be elevated in lead poisoning and hereditary tyrosinemia 1

3. Genetic testing:

   • Only perform after biochemical confirmation of acute porphyria 1
   • Sequence and analyze gene dosage of HMBS (for AIP), PPOX (for VP), CPOX (for HCP), or ALAD (for ALAD deficiency) 1

Diagnostic Algorithm for Cutaneous Porphyrias

1. Initial screening:

   • Plasma porphyrin fluorescence emission spectroscopy 2
   • Total urinary porphyrins 2
   • Whole blood porphyrin analysis (essential for EPP diagnosis) 2

2. Secondary testing:

   • Fecal porphyrin analysis if first-line tests are positive or symptoms persist 2

3. Genetic testing:

   • Only after biochemical confirmation 1
   • For PCT (most common cutaneous porphyria), only 20% have pathogenic UROD variants (familial PCT) 1
   • For EPP, analyze FECH gene and intronic variant c.315-48T>C 1

Treatment Options

Acute Porphyria Attacks

1. Initial management:

   • Mild attacks: Trial of glucose therapy (400g glucose/day for 1-2 days) 3
   • Moderate to severe attacks: Immediate hemin treatment 3

2. Hemin therapy (PANHEMATIN):

   • Dose: 1-4 mg/kg/day for 3-14 days (standard dose 3-4 mg/kg/day) 3
   • Administer via intravenous infusion over at least 30 minutes 3
   • Monitor effectiveness by measuring decreases in urinary ALA, PBG, uroporphyrin, and coproporphyrin 3

3. Supportive care:

   • Eliminate precipitating factors 3
   • Manage symptoms: pain control, treatment of autonomic dysfunction, neuropathy, and encephalopathy 4
   • Provide adequate nutrition and fluid therapy 4

Management of Cutaneous Porphyrias

• Porphyria Cutanea Tarda (PCT):

  • Iron depletion therapy 5
  • Hydroxychloroquine 5
  • Treatment of hepatitis C if present 5

• Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria:

  • α-melanocyte-stimulating hormone analogue to reduce photosensitivity 5

Long-term Management

• During remission of acute porphyrias:

  • Education about precipitating factors for patients and family doctors 4
  • Provide information about online drug lists of safe/unsafe medications 4
  • Genetic screening for family members 1, 4

• For patients with recurrent attacks:

  • Lifestyle evaluation 4
  • Evaluation of hormonal therapy in women 4
  • Consider prophylactic heme therapy 4
  • Liver transplantation for severe recurrent attacks 4

• Long-term complications monitoring:

  • Chronic hypertension 4
  • Chronic kidney insufficiency 4
  • Chronic pain syndrome 4
  • Hepatocellular carcinoma 4

Common Pitfalls to Avoid

• Performing genetic testing without prior biochemical confirmation can lead to false diagnoses 1
• Relying on urinary total porphyrins alone for diagnosing acute porphyria is misleading 1
• Failing to protect samples from light exposure can cause falsely low results 1
• Delaying treatment of moderate to severe acute attacks increases risk of neurological damage 3
• Misinterpreting elevated porphyrins in patients with liver disease, iron deficiency, or lead intoxication as primary porphyria 5