What is the diagnostic workup for Porphyria (a group of disorders that result from a buildup of natural chemicals that produce porphyrin in the body)?

From the Guidelines

The diagnostic workup for porphyria should begin with clinical suspicion based on symptoms, followed by first-line screening tests, including measurement of urinary porphobilinogen (PBG) and aminolevulinic acid (ALA) during an attack, as these tests have high sensitivity and specificity for acute porphyrias 1. The diagnostic approach to porphyria involves a combination of clinical evaluation, biochemical testing, and genetic analysis.

Key Steps in Diagnosis

• Clinical suspicion based on symptoms such as abdominal pain, neuropsychiatric manifestations, and photosensitivity
• First-line screening tests:
  • For acute porphyrias: measure urinary PBG and ALA during an attack
  • For cutaneous porphyrias: examine plasma or urine for elevated porphyrins and their specific patterns
• Second-line testing: quantitative measurements of specific porphyrins in urine, blood, and stool to determine the exact type of porphyria
• Genetic testing to confirm the diagnosis by identifying mutations in specific genes associated with each porphyria type, which is particularly useful for differentiating between porphyrias with similar clinical presentations and for facilitating family investigations 1

Importance of Timing and Sample Handling

Timing is crucial, with samples ideally collected during symptomatic periods when biochemical abnormalities are most pronounced. Proper handling of samples, including protection from light for cutaneous porphyrias, is essential to ensure accurate test results.

Comprehensive Workup and Consultation

A comprehensive workup may also include liver function tests, complete blood count, and electrolytes to assess complications. Given the complexity and rarity of these disorders, consultation with specialists in metabolic disorders or hematology is often necessary 1. Early diagnosis is critical to prevent irreversible neurological damage in acute attacks and to provide appropriate management and care for patients with porphyria.

From the FDA Drug Label

• Before PANHEMATIN therapy is begun, the presence of acute porphyria must be diagnosed using the following criteria:

1. Presence of clinical symptoms suggestive of acute porphyric attack.
2. Quantitative measurement of porphobilinogen (PBG) in urine The single-void urine sample should be refrigerated or frozen without additives and shielded from light for subsequent quantitative δ-aminolevulinic acid (ALA), PBG, and total porphyrin determinations.

The diagnostic workup for porphyria includes:

• Clinical symptoms: Presence of clinical symptoms suggestive of acute porphyric attack
• Quantitative measurement of porphobilinogen (PBG) in urine: Single-void urine sample should be refrigerated or frozen without additives and shielded from light for subsequent quantitative δ-aminolevulinic acid (ALA), PBG, and total porphyrin determinations 2

From the Research

Diagnostic Workup for Porphyria

The diagnostic workup for porphyria involves a series of tests to determine the type and severity of the disorder. The following are some of the key tests and procedures used in the diagnostic workup for porphyria:

• Measurement of urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels to diagnose acute hepatic porphyrias 3
• Porphobilinogen (PBG) quantitation in a random urine sample collected during symptoms to investigate an acute attack 4
• Urine porphyrin excretion (TUP) measurement on the same urine sample as PBG testing 4
• Plasma porphyrin fluorescence emission spectroscopy and random urine sample for TUP to investigate cutaneous porphyria 4
• Whole blood for porphyrin analysis to identify protoporphyria 4
• Faeces collection if first-line tests are positive or if clinical symptoms persist 4

Interpretation of Test Results

The interpretation of test results is crucial in the diagnosis of porphyria. The following are some of the key considerations:

• A more than fivefold elevation of urinary porphobilinogen excretion together with typical symptoms of an acute attack is sufficient to start treatment 5
• The within-subject biological variations of ALA and PBG are 16%-20% in the short-term settings and for PBG, 25% in the long-term setting, giving reference change values of approximately 50% and 70%, respectively 6
• A 2-fold increase in PBG, independent of the baseline concentration, will be detected with a probability >80% and is most likely related to the patient's disease and not caused only by analytical and biological variation 6

Management of Porphyria

The management of porphyria involves a range of strategies, including:

• Awareness and avoidance of triggering factors 7
• Infusions of hemin for severe acute attacks 7
• Maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts, for chronic suppressive therapy 7
• Skin protection and afamelanotide, an α-melanocyte stimulating hormone analog, for erythropoietic protoporphyria (EPP) 7
• Liver transplantation may be necessary for severe EPP-induced liver complications 7