What are the initial steps for diagnosing and managing suspected porphyria, including tests and follow-up care?

Porphyria: When to Suspect, Testing, and Follow-Up

When to Suspect Porphyria

Suspect acute hepatic porphyria in any patient with recurrent severe abdominal pain without an identifiable cause, especially in women aged 15-50 years. 1

Key clinical triggers that should raise suspicion:

• Severe abdominal pain (most common presenting symptom) with negative imaging studies 2
• Neuropsychiatric symptoms including peripheral neuropathy, motor weakness, or psychiatric manifestations 1
• Hyponatremia (occurs in 25-60% of acute attacks) 1
• Symptoms triggered by specific medications, fasting, alcohol, stress, or hormonal changes 1, 3
• Menstrual cycle-related attacks in women (90% of symptomatic patients are women) 4

For cutaneous porphyrias, suspect when patients present with:

• Chronic blistering lesions on sun-exposed areas (hands, face) 1
• Acute painful photosensitivity without scarring 4

Diagnostic Testing

First-Line Test (Most Critical)

Order a random spot urine for ALA, PBG, and creatinine immediately when acute porphyria is suspected. 1

• Normal urine PBG excludes acute hepatic porphyria as the cause of current symptoms 1
• PBG >10 mg/g creatinine (or >5-fold upper limit of normal) confirms acute hepatic porphyria 1
• Results must be normalized to creatinine to avoid false negatives from dilute urine 1
• Testing is most informative during symptomatic periods 1
• A 24-hour urine collection is unnecessary 1

Important caveats:

• If only ALA is elevated (without PBG elevation), check lead level and urine organic acids to rule out lead poisoning and hereditary tyrosinemia 1
• Do NOT use total urine porphyrins as a screening test for acute hepatic porphyria 1
• Short delays in refrigerating or shielding samples from light are unlikely to cause false negatives 1

Confirmatory Testing

Once biochemical diagnosis is confirmed:

• Genetic testing by sequencing HMBS, CPOX, and PPOX genes to identify the specific mutation and determine which acute hepatic porphyria subtype 1
• Genetic testing enables family screening of at-risk relatives 1, 4
• Genetic testing should NOT be used as first-line testing (except in populations with founder mutations) 1

Additional Baseline Testing

After confirming diagnosis, obtain: 1

• Complete blood count and ferritin
• Comprehensive metabolic panel including estimated glomerular filtration rate (eGFR)
• Liver enzymes
• Baseline neurologic examination documenting any motor/sensory deficits

Follow-Up and Monitoring

Patient Classification for Follow-Up Intensity

The American Association for the Study of Liver Diseases classifies patients into four subgroups that determine monitoring frequency: 1, 3

1. Latent genetic carriers (asymptomatic, normal ALA/PBG)
2. Asymptomatic high excretors (no attacks, but ALA/PBG ≥4x upper limit normal)
3. Sporadic attack patients (<4 attacks per year)
4. Recurrent attack patients (≥4 attacks per year)

Annual Monitoring (All Patients)

Every patient with confirmed acute hepatic porphyria requires at least annual monitoring: 1

• Liver enzymes, creatinine, and eGFR
• Liver ultrasound and alpha-fetoprotein every 6 months after age 50 (hepatocellular carcinoma screening) 1
• Iron and ferritin levels 1
• Blood pressure monitoring (hypertension screening) 3
• Urinalysis with protein-to-creatinine ratio 1

More Frequent Monitoring

Recurrent attack patients require closer follow-up with monitoring tailored to attack frequency and complications 1, 3

Patients on prophylactic hemin or givosiran require additional monitoring: 1

• Comprehensive metabolic panel
• Plasma homocysteine
• B12/folate levels
• Amylase/lipase

For givosiran specifically: Test before starting, before each monthly injection for 3 months, then every 3 months if stable, then at least every 6 months 1

Long-Term Complication Screening

Screen for: 1, 3, 4

• Chronic kidney disease (porphyria-associated kidney disease)
• Hepatocellular carcinoma (especially after age 50)
• Hypertension
• Osteoporosis and vitamin D deficiency
• Anemia

Special Populations

Women of childbearing age: 3, 4

• Pre-conception evaluation recommended
• High-risk obstetrical care during pregnancy (50% experience attacks during pregnancy/postpartum)
• Careful contraceptive selection (avoid progestin-containing contraceptives that may trigger attacks)

Critical counseling point: All newly diagnosed patients must receive education about avoiding triggering factors including porphyrinogenic drugs, fasting, alcohol, smoking, and stress management 1, 3