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Acute intermittent porphyria symptoms during the menstrual cycle A. Ahangari, T. Bäckström, E. Innala, C. Andersson and S. Turkmen Department of Clinical Science, Obstetrics and Gynaecology, Umeå Neurosteroid Research Center, Umeå University, Umeå, Sweden
Key words acute intermittent porphyria, PMS/PMDD, progesterone, pain, hormone, symptom cyclicity. Correspondence Sahruh Turkmen, Umeå Neurosteroid Research Center, Building 5B, 5th Floor, Norrlands University Hospital, SE-90185 Umeå, Sweden. Email: [email protected] Received 14 December 2014; accepted 4 April 2015. doi:10.1111/imj.12784
Abstract Background: Acute intermittent porphyria (AIP), a life-threatening form of the disease, is accompanied by several pain, mental and physical symptoms. Aims: In this study, we evaluated the cyclicity of AIP and premenstrual syndrome (PMS) symptoms in 32 women with DNA-diagnosed AIP during their menstrual cycles, in northern Sweden. Methods: The cyclicity of AIP symptoms and differences in them between the follicular and luteal phases, and the cyclicity of each symptom in each individual woman in different phases of her menstrual cycle were analysed with a prospective daily rating questionnaire. PMS symptoms were also evaluated in the patients on a daily rating scale. Results: Of the 32 women, 30 showed significant cyclicity in at least one AIP or PMS symptom (P < 0.05–0.001). Back pain (10/32) was the most frequent AIP pain symptom and sweet craving (10/15) was the most frequent PMS symptom. Pelvic pain (F = 4.823, P = 0.036), irritability (F = 7.399, P = 0.011), cheerfulness (F = 5.563, P = 0.025), sexual desire (F = 8.298, P = 0.007), friendliness (F = 6.157, P = 0.019), breast tenderness (F = 21.888, P = 0.000) and abdominal swelling (F = 16.982, P = 0.000) showed significant cyclicity. Pelvic pain and abdominal swelling (rs = 0.337, P < 0.001) showed the strongest correlation. The age of women with latent AIP was strongly correlated with abdominal swelling during the luteal phase (rs = 0.493, P < 0.01). Conclusion: Our results suggest that the symptoms of AIP patients change during their menstrual cycles.
Introduction Acute intermittent porphyria (AIP) is an autosomal metabolic disorder in which individuals inherent a partial deficiency in porphobilinogen deaminase, the third enzyme in the haem biosynthesis pathway.1 Several specific AIP symptoms occur during attacks, predominantly pain symptoms, and retrospective studies have reported that symptom attacks in women increase during menstruation.2–5 However, there are no prospective reports of porphyria-related symptoms, especially between attacks or in women with latent AIP (LAIP). The prevalence of manifest acute porphyria, predominantly Funding: This study was supported by the Swedish Research Council, Visare Norr, and Västerbottens County Council. Conflict of interest: None. Abbreviations: AIP, acute intermittent porphyria; LAIP, latent AIP; MAIP, manifest AIP; PMDD, premenstrual dysphoric disorder; PMS, premenstrual syndrome; VAS, visual analogue scale.
AIP, is reported to be 1–2/100 000 in Europe,3,6 and Sweden has a higher incidence of AIP (0.51 per year per million and a prevalence of 1/1000) than other European countries.2,4,7,8 Almost half these patients live in the northern part of Sweden.2,4,7 AIP involves the most severe neuro-visceral attacks of all the acute porphyrias.8 Patients, and especially women, with acute porphyrias usually experience long symptomfree periods but in some cases, serious recurrent acute attacks may occur for years.8 There are significant differences in symptomatic AIP between men and women with higher frequency in women.8 In manifest AIP (MAIP), patients experience and report symptoms, whereas patients with LAIP never experience porphyria symptoms and are thus asymptomatic.4 Clinical symptoms related to manifest porphyria are reported by 10–40% of gene carriers.4,9 Acute attacks can start with severe abdominal pain3,5 (in 90–95% of women),5 autonomic dysfunction and motor neuropathy with probable subsequent flaccid paresis,3 and the attacks
© 2015 Royal Australasian College of Physicians
725
Ahangari et al.
can be life-threatening.3,10 These symptoms are followed by weakness, analgesia and paraesthesia in 40–60% of patients.5 Some factors, such as sex hormones,3,5,9,11 drugs,3,9,11 stress,3,9 alcohol,9 infections3,9 and fasting3,9,11 are considered to be important predisposing elements for the manifestation of AIP attacks.9 An analysis by Hift et al. reported that more than 50% of attacks in women with AIP are precipitated by their menstrual cycle.3,9 There are also fewer attacks after menopause.4,12 Therefore, hormonal factors,3 and especially progesterone,2,4,5 seem to play a critical role in AIP.3 These observational studies include only retrospective reports, and no prospective assessment of the symptoms of AIP relative to different phases of the menstrual cycle has been made. Other symptoms vary with the hormonal variations that accompany the menstrual cycle. The symptoms of premenstrual syndrome (PMS) are defined as somatic (breast tenderness, headache, abdominal swelling and limb swelling) or affective/mood symptoms (irritability, anxiety, depression, social isolation, confusion and anger). These symptoms occur during the luteal phase of the menstrual cycle13 and disappear at the beginning of menses, displaying a cyclical pattern. The prevalence of severe PMS was reported to be 5–10%.14 Premenstrual dysphoric disorder (PMDD) is a severe form of PMS, in which most women report severe mood symptoms and often complain of dysfunction in daily life.15 We conducted a prospective daily study of AIP symptoms and other mental and physical symptoms known to vary in severity with the hormonal fluctuations that occur during the menstrual cycle. The aim of this study was to evaluate the symptoms related to AIP and investigate their patterns throughout the menstrual cycle by comparing them in the follicular and luteal phases.
Methods Subjects Among the 190 women with DNA-diagnosed AIP in northern Sweden, 32 volunteered to participate in the study. The women’s mean age was 36.97 ± 0.21 years (range 27–48 years). The patients were considered to have LAIP if they had never experienced any AIP symptom and to have MAIP if they had experienced the characteristic symptoms of AIP at any time. A descriptive research design was used to collect the data concerning the women’s AIP symptoms during their menstrual cycles, so no control group was required. The patient sample was the same as that used in an earlier study of a different topic.2 Written informed consent was obtained
from all the participants before the study commenced. This study was approved by the Regional Ethical Review Board of Umeå, Sweden.
Symptoms The days of the menstrual cycle were recorded by the patients prospectively using a calendar over 1–2 consecutive menstrual cycles and the first day of menstrual bleeding was counted as day 1. Each patient was asked to complete one questionnaire for each day of their menstrual cycles. The questionnaire contained questions regarding AIP pain symptoms (pelvic pain, abdominal pain, back pain and muscle pain) and other AIP symptoms (constipation and weakness in the arms or legs) and also positive mental symptoms (energy, cheerfulness, friendliness and relaxed mood), negative mental symptoms (irritability, mood swings, depression, tenseness, fatigue and sweet craving), physical symptoms (breast tenderness and abdominal swelling) and a question about sexual desire. The symptoms were assessed with a visual analogue scale (VAS) and rated between 0 (no symptoms) and 10 (extreme/unbearable). In this study, we focused on the AIP symptoms of pain (pelvic pain, abdominal pain, back pain, muscle pain), constipation and weakness in the arms or legs. The VAS is a valid tool for assessing pain and PMS/PMDD symptoms.16,17 Questions were added to the VAS concerning constipation and weakness in the arms or legs to construct our questionnaire. Among the abovementioned symptoms, irritability, depression, mood swings, anxiety, abdominal swelling (bloating), breast tenderness, food (sweet) cravings and fatigue are also considered to be symptoms of PMS/ PMDD.14,18,19 The PMS symptoms were evaluated by patients using the daily rating scale, based on the symptoms described by the American College of Obstetricians and Gynecologists, over one menstrual cycle.14 A symptom was defined as significantly cyclic if there was a significant difference in the symptom scores between follicular phase days 5–11 and luteal phase days 21–27, based on the daily ratings during one menstrual cycle. Blood samples for progesterone testing were taken in the morning, twice in the follicular phase (early and late follicular phase between menstrual cycle days 5 to 12 respectively) and three times in the luteal phase (cycle days 16–26, early, mid and late luteal phase). In all patients, mid-cycle serum progesterone concentrations according to the sampling days were used to date ovulation. The cycle was interpreted as an ovulatory menstrual cycle if the luteal phase serum progesterone was
Acute intermittent porphyria symptoms during the menstrual cycle A. Ahangari, T. Bäckström, E. Innala, C. Andersson and S. Turkmen Department of Clinical Science, Obstetrics and Gynaecology, Umeå Neurosteroid Research Center, Umeå University, Umeå, Sweden
Key words acute intermittent porphyria, PMS/PMDD, progesterone, pain, hormone, symptom cyclicity. Correspondence Sahruh Turkmen, Umeå Neurosteroid Research Center, Building 5B, 5th Floor, Norrlands University Hospital, SE-90185 Umeå, Sweden. Email: [email protected] Received 14 December 2014; accepted 4 April 2015. doi:10.1111/imj.12784
Abstract Background: Acute intermittent porphyria (AIP), a life-threatening form of the disease, is accompanied by several pain, mental and physical symptoms. Aims: In this study, we evaluated the cyclicity of AIP and premenstrual syndrome (PMS) symptoms in 32 women with DNA-diagnosed AIP during their menstrual cycles, in northern Sweden. Methods: The cyclicity of AIP symptoms and differences in them between the follicular and luteal phases, and the cyclicity of each symptom in each individual woman in different phases of her menstrual cycle were analysed with a prospective daily rating questionnaire. PMS symptoms were also evaluated in the patients on a daily rating scale. Results: Of the 32 women, 30 showed significant cyclicity in at least one AIP or PMS symptom (P < 0.05–0.001). Back pain (10/32) was the most frequent AIP pain symptom and sweet craving (10/15) was the most frequent PMS symptom. Pelvic pain (F = 4.823, P = 0.036), irritability (F = 7.399, P = 0.011), cheerfulness (F = 5.563, P = 0.025), sexual desire (F = 8.298, P = 0.007), friendliness (F = 6.157, P = 0.019), breast tenderness (F = 21.888, P = 0.000) and abdominal swelling (F = 16.982, P = 0.000) showed significant cyclicity. Pelvic pain and abdominal swelling (rs = 0.337, P < 0.001) showed the strongest correlation. The age of women with latent AIP was strongly correlated with abdominal swelling during the luteal phase (rs = 0.493, P < 0.01). Conclusion: Our results suggest that the symptoms of AIP patients change during their menstrual cycles.
Introduction Acute intermittent porphyria (AIP) is an autosomal metabolic disorder in which individuals inherent a partial deficiency in porphobilinogen deaminase, the third enzyme in the haem biosynthesis pathway.1 Several specific AIP symptoms occur during attacks, predominantly pain symptoms, and retrospective studies have reported that symptom attacks in women increase during menstruation.2–5 However, there are no prospective reports of porphyria-related symptoms, especially between attacks or in women with latent AIP (LAIP). The prevalence of manifest acute porphyria, predominantly Funding: This study was supported by the Swedish Research Council, Visare Norr, and Västerbottens County Council. Conflict of interest: None. Abbreviations: AIP, acute intermittent porphyria; LAIP, latent AIP; MAIP, manifest AIP; PMDD, premenstrual dysphoric disorder; PMS, premenstrual syndrome; VAS, visual analogue scale.
AIP, is reported to be 1–2/100 000 in Europe,3,6 and Sweden has a higher incidence of AIP (0.51 per year per million and a prevalence of 1/1000) than other European countries.2,4,7,8 Almost half these patients live in the northern part of Sweden.2,4,7 AIP involves the most severe neuro-visceral attacks of all the acute porphyrias.8 Patients, and especially women, with acute porphyrias usually experience long symptomfree periods but in some cases, serious recurrent acute attacks may occur for years.8 There are significant differences in symptomatic AIP between men and women with higher frequency in women.8 In manifest AIP (MAIP), patients experience and report symptoms, whereas patients with LAIP never experience porphyria symptoms and are thus asymptomatic.4 Clinical symptoms related to manifest porphyria are reported by 10–40% of gene carriers.4,9 Acute attacks can start with severe abdominal pain3,5 (in 90–95% of women),5 autonomic dysfunction and motor neuropathy with probable subsequent flaccid paresis,3 and the attacks
© 2015 Royal Australasian College of Physicians
725
Ahangari et al.
can be life-threatening.3,10 These symptoms are followed by weakness, analgesia and paraesthesia in 40–60% of patients.5 Some factors, such as sex hormones,3,5,9,11 drugs,3,9,11 stress,3,9 alcohol,9 infections3,9 and fasting3,9,11 are considered to be important predisposing elements for the manifestation of AIP attacks.9 An analysis by Hift et al. reported that more than 50% of attacks in women with AIP are precipitated by their menstrual cycle.3,9 There are also fewer attacks after menopause.4,12 Therefore, hormonal factors,3 and especially progesterone,2,4,5 seem to play a critical role in AIP.3 These observational studies include only retrospective reports, and no prospective assessment of the symptoms of AIP relative to different phases of the menstrual cycle has been made. Other symptoms vary with the hormonal variations that accompany the menstrual cycle. The symptoms of premenstrual syndrome (PMS) are defined as somatic (breast tenderness, headache, abdominal swelling and limb swelling) or affective/mood symptoms (irritability, anxiety, depression, social isolation, confusion and anger). These symptoms occur during the luteal phase of the menstrual cycle13 and disappear at the beginning of menses, displaying a cyclical pattern. The prevalence of severe PMS was reported to be 5–10%.14 Premenstrual dysphoric disorder (PMDD) is a severe form of PMS, in which most women report severe mood symptoms and often complain of dysfunction in daily life.15 We conducted a prospective daily study of AIP symptoms and other mental and physical symptoms known to vary in severity with the hormonal fluctuations that occur during the menstrual cycle. The aim of this study was to evaluate the symptoms related to AIP and investigate their patterns throughout the menstrual cycle by comparing them in the follicular and luteal phases.
Methods Subjects Among the 190 women with DNA-diagnosed AIP in northern Sweden, 32 volunteered to participate in the study. The women’s mean age was 36.97 ± 0.21 years (range 27–48 years). The patients were considered to have LAIP if they had never experienced any AIP symptom and to have MAIP if they had experienced the characteristic symptoms of AIP at any time. A descriptive research design was used to collect the data concerning the women’s AIP symptoms during their menstrual cycles, so no control group was required. The patient sample was the same as that used in an earlier study of a different topic.2 Written informed consent was obtained
from all the participants before the study commenced. This study was approved by the Regional Ethical Review Board of Umeå, Sweden.
Symptoms The days of the menstrual cycle were recorded by the patients prospectively using a calendar over 1–2 consecutive menstrual cycles and the first day of menstrual bleeding was counted as day 1. Each patient was asked to complete one questionnaire for each day of their menstrual cycles. The questionnaire contained questions regarding AIP pain symptoms (pelvic pain, abdominal pain, back pain and muscle pain) and other AIP symptoms (constipation and weakness in the arms or legs) and also positive mental symptoms (energy, cheerfulness, friendliness and relaxed mood), negative mental symptoms (irritability, mood swings, depression, tenseness, fatigue and sweet craving), physical symptoms (breast tenderness and abdominal swelling) and a question about sexual desire. The symptoms were assessed with a visual analogue scale (VAS) and rated between 0 (no symptoms) and 10 (extreme/unbearable). In this study, we focused on the AIP symptoms of pain (pelvic pain, abdominal pain, back pain, muscle pain), constipation and weakness in the arms or legs. The VAS is a valid tool for assessing pain and PMS/PMDD symptoms.16,17 Questions were added to the VAS concerning constipation and weakness in the arms or legs to construct our questionnaire. Among the abovementioned symptoms, irritability, depression, mood swings, anxiety, abdominal swelling (bloating), breast tenderness, food (sweet) cravings and fatigue are also considered to be symptoms of PMS/ PMDD.14,18,19 The PMS symptoms were evaluated by patients using the daily rating scale, based on the symptoms described by the American College of Obstetricians and Gynecologists, over one menstrual cycle.14 A symptom was defined as significantly cyclic if there was a significant difference in the symptom scores between follicular phase days 5–11 and luteal phase days 21–27, based on the daily ratings during one menstrual cycle. Blood samples for progesterone testing were taken in the morning, twice in the follicular phase (early and late follicular phase between menstrual cycle days 5 to 12 respectively) and three times in the luteal phase (cycle days 16–26, early, mid and late luteal phase). In all patients, mid-cycle serum progesterone concentrations according to the sampling days were used to date ovulation. The cycle was interpreted as an ovulatory menstrual cycle if the luteal phase serum progesterone was
