Porphyrias: Clinical Features, Diagnosis, and Management
Clinical Presentation
Women aged 15–50 years presenting with unexplained recurrent severe abdominal pain, nausea, vomiting, constipation, tachycardia, and hypertension should be screened for acute hepatic porphyria (AHP), as approximately 90% of symptomatic patients are women in this demographic. 1, 2
Neurovisceral Symptoms (Acute Hepatic Porphyrias)
- Abdominal pain is the hallmark symptom—severe, unexplained, and often recurrent 1, 3
- Autonomic dysfunction: tachycardia, hypertension, vomiting, constipation 1, 3
- Neurologic manifestations: peripheral neuropathy, muscle weakness, seizures, psychosis 1, 3, 4
- Hyponatremia may occur during acute attacks 3, 4
- Dark urine results from elevated porphobilinogen (PBG) that polymerizes on standing 1
Cutaneous Symptoms (Mixed Porphyrias)
- Photosensitivity with bullous skin lesions occurs in variegate porphyria (VP) and hereditary coproporphyria (HCP), distinguishing them from acute intermittent porphyria (AIP) which has neurovisceral symptoms only 2, 3
- Blistering, hyperpigmentation, hypertrichosis on sun-exposed areas 2
Diagnostic Work-Up
First-Line Biochemical Testing
Measure urinary porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) in a random urine sample normalized to creatinine—this is the definitive first-line test. 2, 1
Critical Testing Parameters
- During an acute attack, urinary ALA and PBG rise to at least 5-fold above the upper limit of normal, allowing straightforward diagnosis 2
- Normal PBG effectively excludes acute porphyria (except the exceedingly rare ALAD-deficiency porphyria with fewer than a dozen cases worldwide) 2, 1
- Results must be normalized to urinary creatinine; when creatinine is below 2 mmol/L, values may appear falsely elevated 2
Sample Handling—Critical Pitfalls
- Protect all samples from light by wrapping tubes in aluminum foil—porphyrins are photosensitive and degrade, producing falsely low or negative results 1, 2
- PBG degrades at room temperature, beginning to decline within 24 hours; prompt processing is essential 2
- Refrigerate or freeze single-void urine samples without additives and shield from light 5
What NOT to Order
- Do not order urinary total porphyrins as a first-line test—it is unhelpful and misleading because mild secondary porphyrinurias are common and lead to overdiagnosis 1, 2
- ALA and PBG are porphyrin precursors and are not included in standard "porphyrin" assays, which quantify only fully formed porphyrins 2
Timing of Testing
- Test during an acute attack when urinary ALA and PBG are maximally elevated 2
- In patients with sporadic attacks, 15%–44% may have normal urinary ALA and PBG when asymptomatic, especially in HCP and VP where metabolite levels fall rapidly after attacks 2
- In AIP, urinary ALA and PBG can remain elevated for months to years after an attack, facilitating retrospective diagnosis 2
- Urine testing can be performed days after an acute attack provided the patient has not received intravenous hemin therapy 2
Subtype Differentiation
- Acute intermittent porphyria (AIP): neurovisceral symptoms only, no photosensitivity 2, 3
- Variegate porphyria (VP) and hereditary coproporphyria (HCP): both acute neurovisceral symptoms AND photosensitive skin lesions 2, 3
- Distinguishing VP from HCP requires measurement of fecal porphyrins and plasma porphyrin fluorescence scanning at specialized reference laboratories 2
Genetic Testing
- Perform genetic testing ONLY after biochemical confirmation—pathogenic variants have low clinical penetrance and are identified in roughly 1 in 1,300–1,785 individuals in the general population without causing disease 2, 1
Acute Management
Initial Assessment and Triage
For moderate to severe attacks (severe or prolonged pain, persistent vomiting, hyponatremia, convulsions, psychosis, neuropathy), immediate hemin treatment is recommended. 5
- Severe attacks require intensive care and strict avoidance of porphyrinogenic drugs 4
- Eliminate triggering factors (certain medications, alcohol, fasting, hormonal changes) 1, 4
Glucose Therapy
- For mild porphyric attacks (mild pain, no vomiting, no paralysis, no hyponatremia, no seizures), a trial of glucose therapy (400 g/day for 1–2 days) is recommended while awaiting hemin treatment or if hemin is unavailable 5, 1
Hemin (Intravenous)—Definitive Acute Treatment
The dose of hemin is 3–4 mg/kg/day IV for 3–14 days; in severe cases this dose may be repeated no earlier than every 12 hours, not exceeding 6 mg/kg in any 24-hour period. 5
Administration Details
- Reconstitute immediately before use with 48 mL Sterile Water for Injection; shake well for 2–3 minutes 5
- Infuse over at least 30 minutes via a separate line 5
- After infusion, flush the vein with 100 mL of 0.9% saline 5
- Terminal filtration through a sterile 0.45 micron or smaller filter is recommended 5
- After first withdrawal from vial, discard any remaining solution—contains no preservative and undergoes rapid chemical decomposition 5
Efficacy
- Clinical response (improvement of symptoms and reduction in pain) occurred in 85.5% (141/165) of treatment courses in open-label studies 5
- All patients experienced a chemical response (normalization of urinary ALA and PBG) 5
- In compassionate use study, physician-assessed clinical response was achieved for all acute attacks in 73% (81/111) of patients 5
- 74% of patients assessed hemin therapy as very successful in treating abdominal pain and other symptoms 5
Monitoring
- Monitor urinary ALA, PBG, uroporphyrin, and coproporphyrin during therapy—effectiveness is demonstrated by a decrease in one or more of these compounds 5
Critical Timing
- Clinical benefit depends on prompt administration—attacks may progress to irreversible neuronal damage 5
- Hemin is intended to prevent an attack from reaching the critical stage of neuronal degeneration and is not effective in repairing existing neuronal damage 5
Chronic Management and Prophylaxis
Risk Stratification
- >90% of symptomatic AHP patients experience only 1 or a few acute attacks in their lifetimes 1, 6
- 3%–5% of patients experience frequent recurrent attacks, typically defined as 4 or more attacks per year 1, 6
Prophylactic Treatment Indications
Prophylactic treatment with hemin IV or givosiran subcutaneous should be considered for patients with 4 or more acute attacks per year. 6, 1
- Patients with recurrent attacks often have no identifiable triggers, though some attacks during the luteal phase are believed to be triggered by progesterone 1
- In prophylaxis study, among 31 patients who received hemin prophylaxis for >1 month, 68% (21/31) did not require subsequent hemin treatment for acute attacks 5
Long-Term Complications in Recurrent Disease
- >50% of patients with recurrent attacks report chronic neurologic symptoms, and 35% have received a diagnosis of neuropathy 1
- Increased risk of hepatocellular carcinoma 1, 6
- Chronic renal failure 6, 2
- Systemic hypertension 6
- Permanent peripheral neuropathy 6
- Markedly impaired quality of life 1, 6, 2
Common Pitfalls and How to Avoid Them
- Delayed diagnosis: Diagnoses of AHPs are often missed, with a delay of more than 15 years from initial presentation 1
- Testing asymptomatic patients first: Always test during or immediately after an acute attack when metabolites are maximally elevated 2
- Ordering wrong tests: Do not order urinary total porphyrins alone—order urinary ALA and PBG normalized to creatinine 1, 2
- Improper sample handling: Failure to protect samples from light and delays in processing lead to falsely negative results 1, 2
- Genetic testing without biochemical confirmation: Pathogenic variants are common in the general population without disease 2, 1
- Delayed hemin administration: Prompt treatment is critical to prevent irreversible neuronal damage 5