How should I diagnose porphyria in a patient with recurrent abdominal pain, neuropsychiatric symptoms (anxiety, confusion, seizures), hyponatremia, and photosensitivity (blistering, hyperpigmentation, hypertrichosis)?

Diagnosing Porphyria

Measure urinary porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) in a random urine sample, normalized to creatinine—this is the definitive first-line test to diagnose acute hepatic porphyria in your patient with recurrent abdominal pain and neuropsychiatric symptoms. 1

Initial Diagnostic Approach

Your patient's constellation of symptoms—recurrent abdominal pain, neuropsychiatric manifestations (anxiety, confusion, seizures), and hyponatremia—is highly suggestive of acute hepatic porphyria (AHP), particularly since approximately 90% of symptomatic patients are women of childbearing age. 1 The photosensitivity with blistering and hyperpigmentation suggests either variegate porphyria (VP) or hereditary coproporphyria (HCP), which can present with both acute neurovisceral attacks and cutaneous manifestations. 1

Specific Biochemical Testing

• Order a random (spot) urine sample measuring ALA, PBG, porphyrins, and creatinine—do NOT order a 24-hour urine collection as it is unnecessary and delays diagnosis. 1

• During an acute attack, both ALA and PBG will be elevated at least 5-fold above the upper limit of normal, making the diagnosis straightforward. 1

• Results must be normalized to urinary creatinine to account for urine concentration differences; interpret results cautiously if creatinine is below 2 mmol/L as they may appear falsely elevated. 1

• A normal PBG level effectively rules out acute porphyria (except for the extremely rare ALAD deficiency porphyria with fewer than a dozen reported cases worldwide). 1

Critical Testing Pitfalls to Avoid

• Do not rely on urinary porphyrins alone for screening—mild elevations in urinary porphyrins (secondary porphyrinurias) are common and frequently lead to incorrect overdiagnosis of porphyria. 1

• Protect all samples from light by covering tubes in aluminum foil, as porphyrins are photosensitive and will degrade, causing falsely low or negative results. 1

• PBG begins to decrease within 24 hours at room temperature, so ensure prompt sample processing. 1

• Be aware that ALA and PBG are porphyrin precursors and are NOT included in standard "porphyrin" tests, which typically measure only fully formed porphyrins by high-performance liquid chromatography. 1

Distinguishing Between Porphyria Types

Once biochemical testing confirms elevated ALA and PBG:

• VP and HCP present with both acute neurovisceral symptoms AND photosensitive skin lesions (blistering, hyperpigmentation, hypertrichosis), matching your patient's presentation. 1

• Acute intermittent porphyria (AIP) causes only neurovisceral symptoms without photosensitivity. 1

• Further differentiation requires measuring fecal porphyrins and plasma porphyrin fluorescence scanning to distinguish VP from HCP, though this is typically done at specialized reference laboratories. 1

Timing Considerations

• Testing is most reliable during an acute attack when ALA and PBG are maximally elevated. 1

• In patients with sporadic attacks, 15-44% may have normal urine ALA and PBG when asymptomatic, particularly in HCP and VP where levels can fall quickly after attacks. 1

• However, in AIP, ALA and PBG can remain elevated for months to years after an acute attack, making retrospective diagnosis easier. 1

• Unless the patient has received intravenous hemin treatment, testing can be performed days after an acute attack. 1

Clinical Context

The triad of hyponatremia, seizures, and abdominal pain should immediately raise suspicion for porphyria. 2, 3 Your patient's neuropsychiatric symptoms (anxiety, confusion, seizures) are classic manifestations that can mimic schizophrenia, conversion disorder, or other psychiatric conditions, leading to diagnostic delays averaging 15 years. 1, 4

After Biochemical Confirmation

• Genetic testing should only be pursued AFTER biochemical confirmation, not as a primary screening tool, since pathogenic variants have low clinical penetrance and are found in 1 in 1,300-1,785 people in the general population without causing disease. 1

• Patients with recurrent attacks (≥4 per year) have markedly impaired quality of life and face increased risk of hepatocellular carcinoma and chronic renal failure, making early diagnosis critical for long-term morbidity and mortality. 1