Studies on the acute porphyrias : with special reference to women’s health
The acute porphyrias are a group of rare inherited disorders of the metabolism of heme. Three acute porphyrias comprise most of the cases: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). All three are inherited in an autosomal dominant pattern and have a very low clinical penetrance.
In a subgroup of individuals with acute porphyria, the imbalance in heme metabolism results in the accumulation of heme precursors, measured as excreted molecules in the urine. A significant accumulation of heme precursors in combination with neurovisceral symptoms such as pain and paresis constitute the acute porphyria attack. In addition to the risk of developing acute attacks, the genetic traits for acute porphyria are associated with increased risk for other comorbidities, most notably hypertensive disease, chronic kidney disease and primary liver cancer.
Despite their inheritance pattern, acute porphyrias have been regarded as affecting women to a greater extent than men. This assumption was initially based on the numerous case reports of patients with severe, life-threatening disease manifestations, almost exclusively female. It has further been strengthened by the fact that women are overrepresented in symptomatic patient cohorts. The mechanisms behind such a skewed disease phenotype pattern are not entirely understood. A correlation between acute porphyria pathophysiology and the fluctuations in the hormones of the gonads, particularly progesterone, has been suggested.
Progesterone fluctuates during the menstrual cycle and has been suggested as a contributing factor in making women more susceptible to acute porphyria manifestations compared to men. Progesterone levels increase manifoldly during pregnancy, and significant morbidity was reported in women with acute porphyria during pregnancy in the past. Administration of large doses of progestogens are part of fertility treatments for which reason they are still not recommended for women with acute porphyria.
We set out to highlight and update the different aspects of women’s health in acute porphyria.
In Study I we report of the clinical and biochemical outcomes of 44 pregnancies in 33 women with acute porphyria. Four women experienced acute attacks during pregnancy and one during the postpartum period. Seven women developed hypertension and four pregnancies ended with pre-eclampsia. The levels of heme precursor excretion were measured in 38 of the pregnancies; 32 showed an increase in the excretion of heme precursors during pregnancy. The study suggests increased risk for pregnancy-related hypertensive disease in acute porphyria and is the first report of increased biochemical activity in women with acute porphyria and asymptomatic pregnancies.
In Study II the outcomes in nine women with acute porphyria that underwent fertility treatments are presented in detail. The treatments were generally well-tolerated, even though several of the agents administered are classified as porphyrinogenic.
In Study III we aimed to expand our observations based on single cases and small patient cohorts to the entire population of women with acute porphyria in Sweden. We combined biochemical and genetic data from the Swedish Porphyria Register with data regarding morbidity and complications from Swedish Medical Register for all women with acute porphyria between 1987 and 2015; 214 women with acute porphyria and 2174 matched comparators were included. Women with acute porphyria presented with a higher risk for pregnancy-induced hypertensive disorder, gestational diabetes, and small-for-gestational-age birth. Those relative risks were higher in women with AIP who had increased excretion of the heme precursor porphobilinogen.
For Study IV, we aimed to study the differences in disease burden by combining data from the Swedish Porphyria Register with an extensive questionnaire. The final analysis set included 534 patients - 298 women and 236 men. Both patient-reported disease outcomes, such as hospitalization, chronic symptoms, and daily life limitations due to porphyria, as well as biochemical markers of active disease showed a female predominance.
List of scientific papers
I. Vassiliou D, Sardh E. Acute hepatic porphyria and maternal health: Clinical and biochemical follow-up of 44 pregnancies. J Intern Med. 2022 Jan; 291(1):81-94.
https://doi.org/10.1111/joim.13376
II. Vassiliou D, Lindén Hirschberg A, Sardh E. Treatment with assisted reproduction technologies in women with acute hepatic porphyria. Acta Obstet Gynecol Scand. 2021 Sep; 100(9):1712-1721.
https://doi.org/10.1111/aogs.14200
III. Mantel Ä*, Vassiliou D*, Lissing M, Stephansson O, Wahlin S, Sardh E. Maternal and fetal outcomes in acute hepatic porphyria: A Swedish National Cohort Study. J Inherit Metab Dis. 2023 Jul;46(4):675-686. *Joint first authors.
https://doi.org/10.1002/jimd.12616
IV. Vassiliou D, Harper P, Spelman T, Lissing M, Floderus Y, Sardh E. Acute porphyria in women: results from a Swedish national survey study. [Manuscript]
History
Defence date
2023-12-15Department
- Department of Molecular Medicine and Surgery
Publisher/Institution
Karolinska InstitutetMain supervisor
Sardh, ElianeCo-supervisors
Harper, Pauline; Floderus, YlvaPublication year
2023Thesis type
- Doctoral thesis
ISBN
978-91-8017-063-5Number of supporting papers
4Language
- eng