What is the approach to a porphyria workup?

Approach to Porphyria Workup

The diagnosis of porphyria requires specific biochemical testing of urine, blood, and feces, with all samples protected from light to prevent degradation and false negative results. 1

Initial Diagnostic Testing

For Suspected Acute Porphyria (Neurovisceral Symptoms)

• Collect a random urine sample during symptoms for:

  • Quantitative porphobilinogen (PBG) measurement (primary test)
  • δ-aminolevulinic acid (ALA) measurement
  • Ensure urinary creatinine is >2 mmol/L for accurate interpretation 2, 1
  • Process PBG samples promptly as PBG is unstable at room temperature 2

• Interpretation:

  • Significantly increased urinary PBG (typically >10× upper limit of normal) confirms acute porphyria during an attack 2
  • Normal PBG rules out acute porphyria as the cause of current symptoms 1
  • ALA is less specific than PBG and can be elevated in lead poisoning and hereditary tyrosinemia 1

For Suspected Cutaneous Porphyria

• Collect:
  • EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy
  • Whole blood for porphyrin analysis (essential to identify protoporphyria)
  • Random urine sample for total urinary porphyrins (TUP) 1, 3

Secondary Testing for Classification

After confirming porphyria with initial tests, determine the specific type:

• For acute hepatic porphyrias (AIP, VP, HCP, ADP):

  • Analyze patterns of porphyrins in urine, plasma, and feces 2
  • Measure coproporphyrin III:I ratio in urine or feces 2
  • Plasma fluorescence emission spectroscopy (particularly valuable for VP) 1

• For cutaneous porphyrias (PCT, EPP, XLEPP, CEP):

  • Specific porphyrin patterns in plasma, urine, and/or feces 1
  • Fecal analysis if first-line tests are positive or symptoms persist 3

Genetic Testing

• Perform genetic testing after biochemical confirmation to:
  • Identify the specific mutation
  • Enable family screening
  • Provide genetic counseling 1
  • Note: Limited value in symptomatic porphyrias due to low clinical penetrance (>90% of heterozygotes remain asymptomatic) 2

Common Pitfalls to Avoid

• Sample handling errors:

  • Failure to protect samples from light
  • Delayed processing of PBG samples
  • Inadequate urine concentration (creatinine <2 mmol/L) 2, 1

• Diagnostic errors:

  • Relying solely on total urinary porphyrins (can be misleading for acute porphyrias)
  • False positives with colorimetric methods
  • False negatives with methenamine hippurate 2
  • Overlooking secondary causes of elevated porphyrins (lead poisoning, liver disease, iron deficiency) 4

• Timing errors:

  • Testing during remission may not exclude porphyria (normal results can occur between attacks) 1
  • Delayed testing after symptom onset (especially for acute attacks) 5

Follow-up Management

• For confirmed acute porphyria:

  • Refer to specialized porphyria services for clinical advice 1
  • Counsel patients about avoiding known precipitating factors (certain drugs, stress, fasting, alcohol, smoking) 2
  • Consider hemin therapy for acute attacks (3-4 mg/kg/day) 5
  • Monitor urinary ALA and PBG levels to assess treatment response 5

• For confirmed cutaneous porphyria:

  • PCT: Consider iron depletion, hydroxychloroquine therapy, and HCV elimination if applicable 4
  • EPP/XLEPP: Consider α-melanocyte-stimulating hormone analogues to reduce sunlight sensitivity 4

Special Considerations

• For family history or latent porphyria investigation:

  • Contact a specialist porphyria laboratory for advice
  • Provide detailed clinical and family information 3

• For patients with recurrent attacks:

  • Consider prophylactic hemin therapy to prevent attacks 5
  • Implement strict avoidance of porphyrinogenic drugs and other precipitating factors 2

By following this systematic approach to porphyria workup, clinicians can achieve timely diagnosis and appropriate management, significantly improving patient outcomes and preventing potentially life-threatening complications.