Acute intermittent porphyria, women and sex hormones. Screening for hepatocellular carcinoma in porphyria

Abstract: Background: Porphyrias are inherited disorders with impaired heme biosynthesis. Acute intermittent porphyria (AIP) is the most common porphyria in Sweden. AIP attacks may be life-threatening. Female sex hormones are regarded as important precipitating factors. Hepatocellular carcinoma (HCC) is a severe complication in the older AIP population.The aim of the thesis was to describe the clinical expression of AIP in women, experience of hormonal contraception and hormonal replacement therapies (HRT) and of pregnancies. Secondly, we evaluated gonadotropin-releasing hormone (GnRH) agonist treatment for prevention of menstrual-cycle-related AIP attacks. Thirdly, we evaluated whether an altered sex-steroid metabolism was present in AIP women compared with controls. Finally, we evaluated the benefit of screening for HCC in AIP in a 15-year follow-up study.Methods and results:In a retrospective population-based study in northern Sweden, 166 female AIP gene carriers ≥18 years of age participated. Manifest AIP (MAIP) was reported in 55%; 82% had severe attacks and 39% had menstrual-cycle-related attacks. Hormonal contraceptives were used by 94, and 12 reported that this precipitated AIP attacks. HRT and local vaginal treatments in menopause did not precipitate AIP attacks. Only 10% reported impairment of AIP symptoms during pregnancy.In the retrospective follow-up study of GnRH-agonist treatment, 11 of 14 women improved during treatment. Porphyria attacks were triggered in two women after estradiol add-back and in 5 of 9 women after progesterone add-back.In the sex-steroid metabolism study, levels of s-progesterone, estradiol, allopregnanolone and pregnanolone during the menstrual cycle in 32 AIP gene carriers were compared with 20 healthy controls. Progesterone metabolism in the AIP group differed from controls. In the AIP group levels of allopregnanolone, but not pregnanolone, were significantly lower.In the prospective HCC screening study AIP gene carriers aged >55 years were included. On average 62 subjects participated during 15 years. HCC was diagnosed in 22 of 180 eligible AIP gene carriers in the region (male:female, 12:10, 73% MAIP). The annual incidence of HCC was 0.8%. The risk of HCC was 64-fold higher than in the general population over 50 years of age in this region, and even higher for AIP women (93-fold). Increased 3- and 5-year survival was seen in the regularly screened AIP group. Liver lab tests were not useful in HCC screening.Conclusion:The clinical expression of AIP in women is pronounced and menstrual-cycle-related attacks are common. Hormonal contraceptives can induce AIP attacks and caution is recommended. GnRH-agonist treatment can ameliorate menstrual-cycle-related attacks of porphyria. Dose findings for GnRH-agonists and add-back regimes, especially for progesterone, are intricate. Progesterone metabolism in the AIP group differs from that in healthy controls. HCC screening in AIP gene carriers >50 years of age enables early diagnosis and a possibility for curative treatments. Annual HCC screening with liver imaging is recommended in AIP gene carriers >50 years of age.