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Acute intermittent porphyria, women and sex hormones. Screening for hepatocellular carcinoma in porphyria
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2010. , 75 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1374
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:umu:diva-36884ISBN: 978-91-7459-088-3 (print)OAI: oai:DiVA.org:umu-36884DiVA: diva2:356573
Public defence
2010-11-05, Sal B, By T9, 9 tr, Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-10-15 Created: 2010-10-13 Last updated: 2010-10-15Bibliographically approved
List of papers
1. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden
Open this publication in new window or tab >>Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden
2003 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 254, no 2, 176-183 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To describe the clinical expression of acute intermittent porphyria (AIP) in women, their use of exogenous sex hormones, and the effects on AIP. DESIGN: A retrospective population-based study. SUBJECTS: All women aged > or =18 years (n = 190) with DNA-diagnosed AIP in northern Sweden. RESULTS: A total of 166 women (87%) participated; 91 (55%) had manifest AIP. Severe attacks were reported by 82%; 39% reported recurrent premenstrual AIP attacks and 22% reported chronic AIP symptoms. Oral hormonal contraceptives had been used by 58% of all these women and by 50 with manifest AIP (57%). Twelve women (24%) associated oral contraceptives as precipitating AIP attacks; in nine cases their first attack. One woman experienced relief from AIP symptoms. On commencing their treatment, 72% of the women with manifest AIP had not yet suffered their first attack. Twenty-two women (25%) aged > or =45 years had used hormonal replacement therapy (HRT) at menopause to remedy climacteric symptoms (the percutaneous route was most frequently used); no AIP attack was precipitated. HRT to remedy vaginal dryness was used by 26 women (28%) aged > or =45 years without triggering an AIP attack. Miscarriages were more frequent in women with manifest AIP (50%) than in the latent group (30%, P = 0.014). CONCLUSIONS: About half of the women with AIP had used oral hormonal contraceptives. As 25% of women with manifest AIP reported attacks associated with such drugs, caution must still be recommended. Menopausal HRT only rarely affected the disorder. Miscarriage was more common amongst women with manifest AIP.

Keyword
acute intermittent porphyria; miscarriage; sex hormone; woman
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-36812 (URN)10.1046/j.1365-2796.2003.01172.x (DOI)12859699 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2017-12-12Bibliographically approved
2. Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria
Open this publication in new window or tab >>Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria
2010 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 89, no 1, 95-100 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To describe the benefits and adverse effects of gonadotropin-releasing hormone (GnRH) agonist treatment for prevention of recurrent menstrual attacks in women with acute intermittent porphyria and variegate porphyria. To describe concomitant add-back therapies with estradiol and progesterone and describe their benefits and adverse effects. DESIGN: A retrospective follow-up with questionnaires, interviews and medical records. SETTING: Out-patient care at the Umeå University Hospital in Sweden. POPULATION: Sixteen Caucasian women with DNA-diagnosed porphyria and menstrual-cycle-related porphyria attacks were treated with GnRH agonists during 1984-2000. Fourteen women participated. The mean age when treatment started was 33 years (17-48 years). The duration of treatment varied between 5 months and 9 years. METHODS: GnRH agonists were administered by the intranasal route or by injections. To reduce menopausal symptoms, add-back therapy with low doses of estradiol was administered, and for endometrial protection progesterone was usually administered. MAIN OUTCOME MEASURES: Treatment effects and adverse events as detected in questionnaires, interviews and medical records. RESULTS: Eleven women reported benefits from GnRH agonist treatment with less intense and/or less frequent porphyria attacks, and in four of them attacks almost disappeared. Two women reported no change. One woman had only temporary improvement. Porphyria attacks were triggered by solely estradiol add-back in two women and in five of nine women when progesterone was given. CONCLUSIONS: 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.

Keyword
Porphyria, menstrual, GnRH agonist therapy, add-back
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-36810 (URN)10.3109/00016340903390729 (DOI)000275251200016 ()20021268 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2017-12-12Bibliographically approved
3. Women with acute intermittent porphyria have a defect in 5α-steroid production during the menstrual cycle
Open this publication in new window or tab >>Women with acute intermittent porphyria have a defect in 5α-steroid production during the menstrual cycle
(English)Manuscript (preprint) (Other academic)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-36813 (URN)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2011-04-01Bibliographically approved
4. Screening for hepatocelular carcinoma in acute intermittent porphyria: A 15-year follow-up in northern Sweden
Open this publication in new window or tab >>Screening for hepatocelular carcinoma in acute intermittent porphyria: A 15-year follow-up in northern Sweden
2011 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 269, no 5, 538-545 p.Article in journal (Other academic) Published
Abstract [en]

Objectives: To evaluate the benefit of screening for hepatocellular carcinoma (HCC) in gene carriers of acute intermittent porphyria (AIP) and estimate the annual incidence of HCC in this group.

Subjects: All AIP gene carriers aged ≥55 years from the northernmost county in Sweden, Norrbotten, were invited for screening in this prospective study every 1–1.5 years during the period 1994–2009. We registered all HCC cases amongst AIP gene carriers in the northern region of Sweden (four counties). We compared gene carriers with repeated screening intervals of <2 years (Group A) with controls (Group B; i.e. gene carriers who had never been screened, those screened for the first time or screened at intervals of >2 years, or dropouts). The screening included radiological examination of the liver and relevant laboratory tests.

Results, A total of 62 AIP subjects participated in the study, comprising 33% of the total AIP population aged >55 years in the northern region of Sweden. HCC was diagnosed in 22 AIP subjects (12 men and 10 women), mean age 69 (59–82) years. Amongst these subjects, 73% had experienced prior AIP attacks. The incidence rate ratio for HCC was 64 (52 in men and 93 in women). There were no cases of hepatitis B/C or alcohol abuse. Liver cirrhosis was rare. Liver resection could be performed in most subjects in Group A. Fourteen patients died of HCC, one in Group A and 13 in Group B. Compared with those who were not screened regularly, screening was associated with improved 3-year and 5-year survival (P = 0.005 and 0.038).

Conclusions, Screening for HCC in carriers of AIP enables early diagnosis and a choice of potentially curative treatments with improved prognosis. We recommend annual screening using liver imaging for AIP gene carriers >50 years of age.

Place, publisher, year, edition, pages
Wiley, 2011
Keyword
acute intermittent porphyria, hepatocellular carcinoma, screening, surveillance
National Category
Family Medicine
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-36817 (URN)10.1111/j.1365-2796.2010.02335.x (DOI)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2017-12-12Bibliographically approved

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