What is the appropriate workup for a patient with elevated porphobilinogen (PBG) levels?

Workup for Elevated Porphobilinogen

When porphobilinogen (PBG) is elevated, immediately confirm the diagnosis of acute hepatic porphyria (AHP) by ensuring PBG levels are at least 5-fold above the upper limit of normal (normalized to creatinine), then proceed with genetic testing to determine the specific AHP type, followed by comprehensive baseline assessment and long-term monitoring protocols. 1, 2

Initial Confirmation and Diagnostic Testing

Verify the Elevation is Significant

• Confirm PBG is elevated ≥5-fold above the upper limit of normal when normalized to creatinine in a spot urine sample—this threshold is diagnostic for an acute porphyria attack 1, 3
• During active attacks, the PBG/creatinine ratio typically increases to more than 10 times the upper limit of normal 3, 2
• A PBG level at the upper limit of normal during ongoing symptoms is NOT consistent with an acute porphyria attack—pursue alternative diagnoses 3, 2
• Ensure proper sample handling by refrigerating or freezing promptly to prevent degradation, and protect all samples from light 2, 4

Quantify Both PBG and ALA

• Measure both porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) levels in the same spot urine sample, normalized to creatinine 1, 2
• Use validated quantitative ion-exchange resin-based methods or LC-MS for PBG measurement 4
• If only ALA is elevated (with normal or slightly increased PBG), immediately check lead levels and urine organic acids to rule out lead poisoning and hereditary tyrosinemia 1, 2
• Elevated PBG (typically more than ALA) suggests acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) 2

Measure Total Urine Porphyrins

• Quantify total urine porphyrins (TUP) on the same urine sample used for PBG/ALA testing 1
• Do NOT use urine total porphyrins as a screening test for AHP—they are not recommended for initial diagnosis 1

Confirmatory Genetic Testing

Identify the Specific AHP Type

• Perform genetic testing by sequencing HMBS, CPOX, PPOX, and ALAD genes to determine which specific acute hepatic porphyria the patient has 1, 2
• This testing directly impacts treatment decisions and enables family screening 2
• Genetic confirmation should be pursued after initial biochemical diagnosis is established 1

Additional Porphyrin Analysis

• Analyze plasma and fecal porphyrins to help differentiate between the specific types of acute porphyrias 1, 2
• Plasma porphyrin fluorescence emission spectroscopy can provide supportive diagnostic information 4

Comprehensive Baseline Assessment

Complete Medical Evaluation

• Obtain detailed medical history focusing on: recurrent severe abdominal pain, neurological symptoms (peripheral motor/sensory deficits, cranial nerve abnormalities), psychiatric symptoms, and triggers (medications, fasting, alcohol, smoking, hormonal changes) 1
• Perform thorough physical examination with specific neurologic assessment to establish baseline for future comparison 1
• Document all current medications and identify any porphyrinogenic drugs that must be discontinued 1

Initial Laboratory Panel

• Liver enzymes (AST, ALT, alkaline phosphatase, bilirubin) 1
• Renal function: creatinine and estimated glomerular filtration rate (eGFR) 1
• Comprehensive metabolic panel 1
• Complete blood count 1

Baseline Imaging

• Liver ultrasound to establish baseline hepatic status 1
• Abdominal imaging as clinically indicated to exclude other causes of symptoms 1

Patient Classification for Management

Classify the patient into one of four categories to guide ongoing management strategy 1, 2:

1. Latent genetic mutation carriers: Asymptomatic with normal ALA/PBG levels 1
2. Asymptomatic high excretors (ASHE): No acute attacks but biochemically active with ALA and PBG ≥4 times upper limit of normal 1
3. Sporadic attack patients: Infrequent acute attacks (<4 per year) 1
4. Recurrent attack patients: Frequent attacks (≥4 per year) requiring consideration for prophylactic therapy 1

Long-Term Monitoring Protocol

Annual Monitoring for All Confirmed AHP Patients

• Liver enzymes, creatinine, and eGFR annually 1, 2
• Liver ultrasound annually 1, 2
• α-fetoprotein every 6 months after age 50 due to significantly increased hepatocellular carcinoma (HCC) risk 1, 2
• Blood pressure monitoring for hypertension 1
• Assessment for chronic complications: neuropathy, chronic kidney disease, chronic symptoms (pain, fatigue, nausea) 1

Additional Monitoring for Patients on Treatment

For patients receiving prophylactic hemin therapy: 1, 2

• Iron and ferritin levels
• Comprehensive metabolic panel
• Plasma homocysteine
• Urinalysis with urinary protein-to-creatinine ratio
• B12/folate levels
• Amylase/lipase

For patients on givosiran: 1, 2

• Perform comprehensive metabolic panel, plasma homocysteine, urinalysis, B12/folate, and amylase/lipase before starting givosiran
• Repeat these tests before each monthly injection for the first 3 months
• If stable and well-tolerated, repeat every 3 months for the next year
• Subsequently monitor at least every 6 months

Critical Pitfalls to Avoid

• Dilute urine samples can cause false-negative results—always normalize PBG to creatinine and request repeat sample if urine creatinine <2 mmol/L 2, 4
• Delayed sample processing affects accuracy—refrigerate or freeze samples immediately and protect from light 2, 4
• Do not dismiss mildly elevated PBG during remission—PBG can be persistently raised between attacks and even in asymptomatic carriers, requiring individualized interpretation by comparing acute phase values to the patient's baseline 5
• Testing during asymptomatic periods may miss the diagnosis—testing is most informative when patients are symptomatic 1
• Normal PBG during symptoms rules out AHP (except for the extremely rare ALAD deficiency porphyria where only ALA is elevated) 3, 2