Diagnosis & testing
Diagnosis & testing
Diagnosis & testing
EPP & XLP are rare and symptoms can be difficult to detect, leading to delays in diagnosis1
Patients may present with little or no visible skin damage, contributing to frequent misdiagnosis and delayed diagnosis1
Phototoxic skin reactions can be excruciating, yet visible signs may be absent even during a severe episode. When present, typical cutaneous findings are broad and nonspecific. In a large cohort of 226 patients with EPP or XLP, the most common visible skin change reported was swelling (86%), followed by redness (48%).1-3
EPP and XLP also go undetected in routine laboratory testing, since the definitive diagnostic test—total erythrocyte protoporphyrin—is not part of the standard workup for photosensitivity.1,4
In a large cohort of patients with EPP or XLP (N=226)3:
Less than 50% of patients reported skin redness with phototoxic pain.3
40% of patients had no history of chronic skin changes.3
Additional factors may contribute to diagnostic delay in EPP and XLP1,4,5
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Patients face an average delay of 13 years from initial symptoms to diagnosis, underscoring the need for increased awareness of EPP and XLP.1,5
When to suspect EPP or XLP
When light-induced pain outweighs visible skin damage, EPP or XLP may be the cause
The following clinical features should raise suspicion for EPP and XLP1,4,6:
- Cutaneous photosensitivity beginning in infancy/childhood
- Prodromal itching and burning on exposure to sun/visible light, followed by increasingly severe pain
- May be accompanied by edema, erythema, and/or petechia
- Most commonly seen on the dorsum of the hands and face
- Symptoms may seem out of proportion to skin changes or lack thereof
EPP and XLP can be readily diagnosed or ruled out by laboratory testing of erythrocyte PPIX levels.4
Avoiding common diagnostic pitfalls
Reliable, repeated measurements of erythrocyte protoporphyrin levels are required for the diagnosis and subsequent management of patients with EPP and XLP. Historically, this necessity has been challenged by the lack of standardization for PPIX testing among laboratories in the US. Critical steps toward harmonizing diagnostic testing include the recent publication of the 2023 Guidelines for EPP and XLP, which establish a standardized framework for evidence-based diagnosis and testing across clinical settings.1,4
The guidelines also provide recommendations on navigating common testing pitfalls to ensure accurate evaluation of EPP and XLP. Some of these potential pitfalls and best practices are highlighted below.4
Best practices:
Total erythrocyte protoporphyrin, including proportions of metal-free and zinc-bound protoporphyrin, is the recommended test for diagnosis of protoporphyria4- Significantly elevated total erythrocyte protoporphyrin (>3x ULN) and majority metal-free (>90% in EPP and ~50%-85% in XLP) is consistent with diagnosis of protoporphyria4
- Accurate testing reports should only refer to total erythrocyte protoporphyrin, zinc protoporphyrin, and metal-free protoporphyrin1
- Genetic testing is recommended to confirm the diagnosis and distinguish between EPP and XLP4
Potential pitfalls:
Mild or moderate elevations in total erythrocyte protoporphyrin are not consistent with diagnosis4- Some laboratories report “free erythrocyte protoporphyrin” (FEP) levels that only reflect zinc protoporphyrin, which may not be elevated in EPP or XLP4
- Genetic testing without biochemical confirmation is discouraged because it may yield uncertain results, including variants of unknown significance or cases with no causative variant identified4
Establishing a diagnosis of EPP or XLP
An accurate diagnosis can provide clarity and validation for patients after many years of painful, unexplained symptoms5,7
The 2023 Evidence-Based Consensus Guidelines for EPP and XLP provide recommendations for appropriate diagnostic testing and interpretation of findings.4
Guidelines for the diagnosis of EPP or XLP
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Primary diagnostic test
Total erythrocyte protoporphyrin with metal-free erythrocyte protoporphyrin fraction4
Confirmatory findings:
- Substantially elevated total erythrocyte protoporphyrin (>3x ULN) and majority metal-free is consistent with diagnosis4
Follow-up tests
Additional testing is recommended to distinguish between EPP and XLP4
Recommended follow-up tests:
- Molecular analysis of FECH and ALAS24
- Percent metal-free versus zinc-bound erythrocyte protoporphyrin4
EPP
Findings consistent with EPP:
- >90% metal-free erythrocyte protoporphyrin4
- Loss-of-function variants in FECH 4
XLP
Findings consistent with XLP:
- 50%-85% metal-free erythrocyte protoporphyrin4
- ~15%-50% zinc-bound erythrocyte protoporphyrin1
- Gain-of-function variants in ALAS24
Multiple laboratories offer PPIX testing
Per the 2023 Guidelines for EPP and XLP, laboratories that can accurately fractionate metal-free and zinc-bound protoporphyrins are recommended to establish the diagnosis and monitor PPIX levels.4
PPIX testing reference guide
| Laboratory | Test Name | Test Code |
|---|---|---|
| ARUP Laboratories8 | Erythrocyte Porphyrin, Whole Blood | 0020610 |
| Labcorp9 | Porphyrins Evaluation, Whole Blood | 815306 |
Mayo Clinic Laboratories10,11 | Protoporphyrins, Fractionation, Whole Blood Protoporphyrins, Fractionation, RBC | PPFE PPFWE |
| Quest Diagnostics12 | Erythrocyte Porphyrin, Whole Blood | 39777 |
Galveston Porphyria Laboratory13 University of Texas Medical Branch (UTMB) | Porphyrins, Erythrocytes | 84202 |
This list is being provided for informational purposes only. Disc Medicine does not endorse or recommend any laboratory listed and is not responsible for updating the information provided.
Resources for physicians
2023 Diagnosis and Management Guidelines
Evidence-based consensus guidelines for the diagnosis and management of EPP and XLP
2024 Liver Dysfunction Guidelines
Evidence-based consensus guidelines for the diagnosis and management of liver dysfunction in EPP and XLP
United Porphyrias Association (UPA)
A national advocacy group that offers expert-backed information and resources to improve porphyria awareness and care
American Porphyria Foundation (APF)
A leading resource for porphyria education, advocacy, and support, including clinician tools and materials
American Porphyrias Expert Collaborative (APEX)
A multidisciplinary group of porphyria specialists coordinating with the UPA to provide peer-to-peer consults
The Porphyrias Consortium
A NIH-supported research network advancing clinical knowledge and innovations in care for the porphyrias
Resources are provided for educational purposes only. Disc Medicine is not responsible for the content of linked sites.
Patients should undergo a thorough baseline evaluation2
Early diagnosis of EPP or XLP followed by a comprehensive initial assessment is critical to identify and mitigate the possibility of serious long-term complications. This is particularly relevant given limited understanding of the natural history of EPP- and XLP-related liver disease and its associated risk factors.2,14,15
These assessments are recommended
at the time of diagnosis and at least yearly thereafter4
- Total erythrocyte protoporphyrin
- Liver biochemistries, including aspartate aminotransferase, alanine aminotransferase, total bilirubin, and alkaline phosphatase
- Iron panel, including iron, total iron binding capacity, and ferritin
- 25-OH vitamin D level
- Complete blood count, including hemoglobin values
Further evaluation is needed if liver chemistries are abnormal16
Patients with abnormal liver chemistries should be evaluated for evidence of EPP- or XLP-related liver dysfunction and alternative or co-existing causes of liver disease.
For detailed guidance on the workup of patients with evidence of liver dysfunction, refer to the 2024 Evidence-Based Consensus Guidelines for Liver Dysfunction in EPP and XLP.