A Prospective, Blinded Study of Symptom Prevalence and Specificity of Porphyrin Precursors in Carriers of Acute Hepatic Porphyria

This study aimed to characterise symptoms and assess the prevalence of elevated urine porphyrin precursors in first-degree relatives of acute hepatic porphyria (AHP) patients who have never experienced acute attacks and had no previous AHP genetic or biochemical testing. 149 first-degree relatives of confirmed AHP patients, previously unscreened for the family mutation, were recruited. All underwent genetic analysis, with 143 completing a study questionnaire and 118 undergoing urine analysis for delta aminolevulinic acid (ALA) and porphobilinogen (PBG). The questionnaire focused on symptoms, medical and family history, and quality of life. The study included 79 AHP mutation carriers and 70 non-carriers. Carriers had significantly higher ALA (6.98 vs. 2.21 mg/g creatinine) and PBG levels (9.17 vs. 1.31 mg/g creatinine) than non-carriers. Female carriers showed higher ALA (9.29 vs. 3.07 mg/g creatinine) and PBG levels (12.71 vs. 3.16 mg/g creatinine) than male carriers. Porphyria-related symptoms were reported by 27% (21/77) of carriers compared to 15% (10/66) of non-carriers, with carriers more likely to report dark urine and prolonged symptoms. Finally, 30.8% of carriers were asymptomatic high excreters (ASHE) with PBG levels exceeding four times the upper limit of normal (ULN). Significant differences in porphyrin precursor excretion and symptom profiles were found between AHP mutation carriers and controls, as well as between female and male carriers. Female carriers are more likely to excrete porphyrin metabolites above the normal range. A larger than expected number of undiagnosed carriers are ASHE with levels greater than four times the ULN.