What are the diagnostic criteria and management options for porphyria?

Diagnosis of Porphyria

For suspected acute porphyria, immediately order a random spot urine for ALA, PBG, and creatinine—a PBG level >10 mg/g creatinine (or >5-fold upper limit of normal) confirms the diagnosis, while normal PBG excludes acute hepatic porphyria as the cause of current symptoms. 1, 2

Clinical Scenarios Requiring Porphyria Testing

Acute Neurovisceral Symptoms

• Suspect acute hepatic porphyria (AHP) in patients with recurrent severe abdominal pain without identifiable cause, particularly in women aged 15-50 years. 1, 2
• Consider the diagnosis when patients present with neuropsychiatric symptoms including peripheral neuropathy, motor weakness, or psychiatric manifestations. 2
• Hyponatremia occurs in 25-60% of acute attacks and should heighten suspicion. 2
• Symptoms may be triggered by specific medications, fasting, alcohol, stress, or hormonal changes. 2

Cutaneous Symptoms

• For patients with cutaneous symptoms suggestive of porphyria cutanea tarda (PCT), plasma fluorescence scanning is recommended as first-line analysis. 3
• PCT typically presents with skin photosensitivity and blistering lesions. 4

Diagnostic Algorithm for Acute Porphyria

Step 1: Initial Biochemical Testing

The key diagnostic test is a spot urine for ALA, PBG, porphyrins, and creatinine. 1

• Testing is most informative when performed while patients are symptomatic. 1
• The sample should be refrigerated or frozen without additives and shielded from light. 5
• During an acute attack, the PBG/creatinine ratio is typically increased to more than 10 times the upper limit of normal. 1
• If measured by mass spectrometry (which has lower detection limits), a result above 10 μmol/mmol creatinine is expected. 1

Step 2: Interpretation of Results

• PBG >10 mg/g creatinine confirms acute hepatic porphyria. 1, 2
• Normal urine PBG excludes acute hepatic porphyria as the cause of current symptoms. 1, 2
• If only ALA is elevated without PBG elevation, check lead level and urine organic acids to rule out lead poisoning and hereditary tyrosinemia. 1

Common pitfall: Do not use urine total porphyrins as a screening test for AHP—this is not recommended and can lead to misdiagnosis. 1

Step 3: Confirmatory Testing

Once biochemical diagnosis is confirmed, proceed with genetic testing by sequencing HMBS, CPOX, and PPOX genes to determine the specific type of acute porphyria. 1

• Genetic testing helps differentiate between acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP). 1
• For family investigations, genetic analysis is preferred when available. 1
• Enzyme activity assays (HMBS activity for AIP) can be performed but may show overlap between healthy individuals and affected patients, making genetic analysis more reliable. 1

Diagnostic Algorithm for Porphyria Cutanea Tarda

Step 1: Biochemical Testing

Fractionation of porphyrins in urine is the standard approach for investigating potential PCT diagnosis. 3

• PCT is characterized by elevated uro- and heptacarboxyl porphyrins in urine. 3
• Samples must be protected from light to avoid falsely low results. 3
• Hepta-, penta-, and isocoproporphyrins predominate in feces. 3

Step 2: Special Considerations

• In patients with kidney failure, fractionation of porphyrins in plasma may facilitate diagnosis. 3
• Measurement of uroporphyrinogen decarboxylase (UROD) activity in erythrocytes can help differentiate between sporadic (type I) and familial (type II) PCT. 3

Step 3: Confirmatory Testing

Genetic testing for UROD gene mutations should be considered to differentiate between sporadic and familial PCT. 3

Common pitfall: Never rely solely on clinical presentation without biochemical confirmation, and avoid using only total urine porphyrin tests without fractionation. 3

Essential Pre-Analytical Requirements

Relevant clinical information is essential for correct test interpretation. 1

Specialist laboratories should provide dedicated request forms that include:

• Current symptom status and date of symptom presentation 1
• List of symptoms to select from 1
• Family history details including type of porphyria, relationship to proband, and known genetic variants 1
• Information on triggering factors (medications, fasting, hormonal changes) 1

Differential Diagnosis Considerations

• Consider pseudoporphyria in the differential diagnosis of PCT—it mimics PCT clinically but lacks characteristic biochemical findings. 3
• Secondary elevated urinary or blood porphyrins can occur in liver diseases, iron deficiency, and lead intoxication without true porphyria. 4
• In patients with only ALA elevation, lead poisoning and hereditary tyrosinemia must be excluded. 1

Monitoring After Diagnosis

Monitor urinary concentrations of ALA, PBG, uroporphyrin, and coproporphyrin during treatment—effectiveness is demonstrated by a decrease in one or more of these compounds. 5

• Every patient with confirmed acute hepatic porphyria requires at least annual monitoring including liver enzymes, creatinine, and eGFR. 1, 2
• Screen for long-term complications including chronic kidney disease, hepatocellular carcinoma, hypertension, osteoporosis, vitamin D deficiency, and anemia. 2
• Patients on prophylactic hemin or givosiran require additional monitoring including comprehensive metabolic panel, plasma homocysteine, B12/folate levels, and amylase/lipase. 1, 2