Acute hepatic porphyria carriers need monitoring, study says
People with genetic mutation may show subtle signs even absent acute attacks
People with genetic mutations that cause acute hepatic porphyria (AHP) who have never experienced acute disease attacks are still at an elevated risk of showing subtle signs of the disease, a study found.
Among undiagnosed first-degree family members of AHP patients, those who tested positive for a disease-causing mutation were more likely to have elevated porphyrin precursors and non-specific symptoms than those without such mutations. This could potentially leave them vulnerable to future complications.
“These findings highlight the importance of screening individuals with a family history of AHP, even if they have never experienced an acute attack,” the researchers wrote.
The study, “A Prospective, Blinded Study of Symptom Prevalence and Specificity of Porphyrin Precursors in Carriers of Acute Hepatic Porphyria,” was published in Liver International.
People with porphyria have genetic mutations that lead to a deficiency in enzymes needed to produce heme, the molecule that enables red blood cells to transport oxygen through the body. A disruption in heme production results in the toxic accumulation of intermediate molecules used to make heme, known as porphyrins and their precursors, in the liver and bloodstream, causing porphyria symptoms.
Mutations and attacks
AHP encompasses three common types — acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria — that are all characterized by the accumulation of the porphyria precursors delta-aminolevuliic acid (ALA) and porphobilinogen (PBG).
Patients experience sudden and sometimes severe symptom attacks characterized by gastrointestinal and neurological issues, which are often triggered by environmental factors like stress, medication, or diet.
A subset of people with AHP-causing mutations have persistently high levels of porphyrin precursors in their urine, but have not experienced acute disease attacks. But such people, called asymptomatic high excreters (ASHE), could still be at an increased risk of future attacks or may experience chronic issues related to porphyrin precursor elevations.
To learn more about this group, a team of scientists in the U.S. looked for disease-causing mutations among 149 first-degree relatives of confirmed AHP patients who hadn’t had genetic testing or experienced an acute porphyria attack.
Participants had a mean age of 44.3, and 63.8% were female. A total of 79 people (53%) were found to carry an AHP-causing mutation, while the remaining 70 (47%) were non-carriers and were used as a control group. Participants were asked to complete symptom questionnaires and provide urine samples to measure ALA and PBG levels.
Available urine test results showed that ALA and PBG levels were significantly higher in mutation carriers than in the control group.
Women vs. men
“As women are far more likely than men to have symptomatic acute attacks, we examined potential sex differences in porphyrin precursor levels,” the researchers wrote.
They found that female mutation carriers also had significantly higher ALA and PBG levels than male mutation carriers, which is “consistent with the importance of sex hormones in AHP,” the researchers wrote.
Of the 143 participants who completed symptom questionnaires, a higher proportion of mutation carriers reported nonspecific symptoms compared with non-carriers (27% vs. 15%).
Dark urine, a known AHP manifestation, was the only symptom that was significantly more frequent among carriers. Mutation carriers were also more likely to experience symptoms that lasted several days to months longer than controls.
“AHP may underlie minor but recurrent symptoms in carriers who have never experienced an acute attack,” the researchers wrote.
Yet there were no significant differences in urine porphyrin precursor levels between carriers with symptoms (symptomatic) and those without symptoms (asymptomatic).
Nearly a third of mutation carriers (30.8%), but none of the control group, were classified as ASHE, with urine PBG levels more than four times the upper limit of normal. This group difference was statistically significant.
ASHE status occurred more often in female carriers than in male carriers (38% vs. 17.4%), with significantly higher average PBG levels in females.
A higher proportion of symptomatic carriers were high PBG excreters relative to asymptomatic carriers (40% vs. 25.6%), but this difference failed to reach statistical significance.
In another analysis, the researchers examined whether the increased proportion of ASHE among mutation carriers could be related to the disease severity of their first-degree relatives with confirmed AHP. However, no significant relationships were observed between urine PBG levels of mutation carriers and the disease severity of their relatives with AHP.
“We identified significant differences in porphyrin precursor excretion levels and symptom profiles between carriers and controls, and between females and males,” the researchers wrote.
While it is not established whether ASHE carriers are at a risk for long-term complications related to AHP, such individuals should be carefully monitored, they said.
“Carriers identified in families through genetic analysis require biochemical testing to determine if previous unexplained … symptoms could have been due to porphyria and to predict the future risk of developing acute attacks,” the team concluded.
About the Author
