Orphanet Journal of Rare Diseases | Phenotypic and Diagnostic Patterns of Acute Hepatic Porphyria

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This study reviewed the clinical data of 45 patients suspected of having Acute Hepatic Porphyria (AHP), revealing phenotypic differences of AHP across genders and races, and indicating that psychiatric and gynecological diseases are positively associated with AHP, while certain autoimmune diseases and diabetes show negative associations. The study emphasizes the importance of early recognition and multidisciplinary collaboration in diagnosing AHP, especially in atypical populations.

 

Literature Overview
The article, titled Recognizing and diagnosing acute hepatic porphyria in atypical patient populations, published in the Orphanet Journal of Rare Diseases, summarizes clinical data from 45 patients suspected of having AHP between 2019 and 2022 at the University of California, Los Angeles (UCLA). It analyzes correlations between phenotypes, demographic characteristics, and comorbidities. The article notes that AHP is more frequently diagnosed in women and white individuals, but significant underdiagnosis may occur in non-white and male populations, possibly due to lack of multidisciplinary involvement and testing opportunities.

Background Knowledge
Acute Hepatic Porphyria (AHP) is a group of rare inherited metabolic disorders caused by mutations in genes involved in the heme biosynthesis pathway. These include AIP (HMBS mutation), VP (PPOX mutation), and HCP (CPOX mutation). AHP is characterized by recurrent abdominal pain, neurological symptoms, and psychiatric manifestations, often leading to misdiagnosis as other functional or structural diseases. Despite available genetic and urinary biochemical tests, the average diagnostic delay for AHP remains as high as 10–15 years. Current diagnostic criteria are primarily based on data from white females, with limited systematic studies in atypical populations such as males and minority ethnic groups. Moreover, AHP-associated mutations may lead to elevated urinary d-ALA and PBG levels, but not all patients show these increases during acute attacks, further complicating diagnosis. This study fills a critical gap in phenotypic characterization across genders and ethnicities and highlights the importance of multidisciplinary collaboration and early testing.

 

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Research Methods and Experiments
The study used a retrospective cohort design, including 45 patients evaluated for AHP at the UCLA Health system between 2019 and 2022. Through manual chart review, patients were classified into AHP+ (27 cases) and AHP- (18 cases), and their demographics, clinical features, biochemical test results, genetic findings, and comorbidities were analyzed. The study also compared phenotypic differences among AHP subtypes (AIP, VP, HCP) and evaluated the efficiency of various diagnostic pathways and testing methods.

Key Findings and Insights

• Among AHP+ patients, 81% were female and 19% were male, with no significant difference in gender distribution compared to AHP- patients.
• All Hispanic or Latino patients in the AHP+ group were correctly diagnosed, whereas none of the Asian patients in the AHP- group were missed.
• 52% of AHP+ patients reported psychiatric history, compared to 28% in the AHP- group, though not statistically significant.
• 52% of AHP+ patients had gynecological comorbidities, significantly higher than the 11% in the AHP- group (p=0.048).
• Urinary biochemical tests showed similar positive rates during acute and non-acute phases (both 50%), suggesting that the timing of testing does not significantly affect diagnostic yield.
• Combining genetic and biochemical testing significantly improves diagnostic accuracy; reliance on single methods increases the risk of missed diagnosis.
• Approximately 30% of AHP+ patients had genetic mutations but negative urinary biochemistry, indicating that biochemical-only testing may underestimate AHP prevalence.
• 40% of male AHP+ patients had neurodevelopmental disorders, significantly higher than in females (p=0.028).
• The study recommends increased AHP screening in gynecological and psychiatric clinics to reduce misdiagnosis and delays.

Implications and Future Directions
This study underscores the importance of identifying AHP in atypical populations, such as males and minority ethnic groups, and suggests updating clinical screening guidelines and enhancing multidisciplinary collaboration to improve early diagnosis. Future studies should focus on AHP manifestations in non-white and male patients and optimize combinations of biochemical and genetic tests to reduce diagnostic delays.

 

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Conclusion
Acute Hepatic Porphyria (AHP) is a frequently misdiagnosed rare disease, especially in atypical populations such as males and non-white individuals. The study found that gynecological and psychiatric comorbidities were significantly higher in AHP+ patients compared to AHP- patients, suggesting these specialties may play a key role in AHP screening. In addition, urinary biochemical markers showed similar diagnostic value during acute and non-acute phases, indicating that a single test at any time point may not be sufficient to exclude AHP. Future research should focus on AHP in these underrepresented groups, update screening recommendations, and enhance multidisciplinary collaboration for earlier diagnosis and intervention. The study also highlights the critical role of genetic testing in patients with negative biochemical markers but persistent symptoms, offering new diagnostic insights for clinicians.

 

Katharina Schmolly, Vivek Rudrapatna, and Simon Beaven. Recommendations for recognizing and diagnosing Acute Hepatic Porphyria in atypical patient populations. Orphanet Journal of Rare Diseases.