Introduction
Porphyria cutanea tarda (PCT) is the most common form of porphyria worldwide, with an estimated prevalence of symptomatic disease of 10:100000 [
1,
2]. The disease is caused by an inherited (familial PCT) or acquired (sporadic PCT) defect in the haem biosynthesis enzyme uroporphyrinogen decarboxylase (UROD), which leads to excess production of uroporphyrinogen and other carboxylated porphyrinogens in the liver. Accumulation of the corresponding water-soluble porphyrins in the skin causes cutaneous photosensitivity [
3].
Clinically, the condition is characterized by skin fragility, blistering, milia, hypertrichosis and hyperpigmentation on sun-exposed areas. Familial PCT is inherited in an autosomal dominant pattern with low clinical penetrance and has a higher prevalence in Norway than other countries because of founder mutations [
4]. Susceptibility factors for both PCT types are iron overload, hepatic infections—in particular, hepatitis C—high alcohol consumption, HIV, smoking and the use of oestrogens [
4‐
6]. PCT may become symptomatic at any age, but typically the age of symptom debut is middle-age [
1]. Treatment usually comprises weekly or biweekly phlebotomy to reduce the iron overload or low-dose chloroquine, which mobilizes porphyrins from the liver, or a combination of the two [
5,
7]. Treatment usually leads to resolution of blistering within two to four months, but complete clinical and biochemical remission may take up to 13 months [
7,
8]. Prognosis is good with an estimated relapse rate of 5–17 per 100 person years [
3]. Annual follow-up visits are recommended to avoid and detect relapses, and these visits should include clinical evaluation, assessment of patient compliance with control of susceptibility factors, and measurement of iron and porphyrin levels [
3,
5].
Generally, optimal therapeutic outcomes and patient satisfaction require knowledge of patients’ concerns and expectations. Such subjective perspectives must be evaluated using patient reported outcome (PRO) data. For dermatological diseases, the evaluation of quality of life (QoL) is particularly important because of the visible aspect of these conditions and the potential psychological impact [
9]. Our previous work in patients with PCT found that, at their worst, PCT symptoms can be very dramatic and patients may perceive PCT as a chronic and systemic disease [
10,
11]. To our knowledge, the present study is the largest sample of PCT patients surveyed about health-related QoL (HRQoL), and only one previous study on QoL in people with PCT has been published. However, this included only a small number of participants (
n = 12) who most likely were in clinical remission [
12]. This highlights the need for further studies into HRQoL and the use of PRO in patients with PCT.
The aims of the present study were to describe HRQoL, symptoms, susceptibility factors, disease activity and treatment in patients with PCT, and investigate the association between these factors.
Discussion
One of the aims of our study was to describe HRQoL in people with PCT, and to the best of our knowledge this is the largest sample of PCT patients surveyed about their HRQoL. We used a standardized measure of HRQoL, and compared scores with the US norms. The PCS and MCS did not indicate a lower HRQoL in the overall PCT group. The appropriateness of using US-derived scoring algorithms has been demonstrated in large general population samples from nine countries, including Norway ([
14] p. 42). The SF-12 is a generic instrument that gives us the opportunity to compare HRQoL in different disease groups. To our knowledge, however, only few studies have published scores from SF-12 in other relevant skin diseases [
19‐
23]. It is a general problem that a clear presentation of the scoring algorithms are missing, resulting in erroneous conclusions because of the mixing of T-scores and 0–100 scores ([
14] p. 164). This makes comparisons with our findings difficult. However, a cross-sectional study in patients suffering from chronic plaque psoriasis, reported an identical mean T-score of MCS, but a lower PCS T-score, compared to our sample [
19]. This indicates that the PCT patients’ mental aspect of HRQoL are in line with the psoriasis study.
Analysis of the eight health domains showed that PCT patients had lower scores for general health (mean 45) and emotional role (mean 46) (Fig.
1) than the US norm. It is possible that underlying health issues (of unknown cause in this sample) act as susceptibility factors for PCT or are associated with PCT. Comorbid health conditions were, however, not assessed, and all the reported symptoms may not be associated with PCT.
In the overall group, we observed a moderate negative correlation between reported symptoms of PCT and physical and mental summary scores, as well as the six single domains. In men, the associations between symptoms and both PCS (
r =
−.614,
p < 0.01), and general health (
r =
−.574,
p < 0.01) was strong (Table
3). Previous research has not supported an association between PCT symptoms and porphyria-related distress [
11], and another study concluded that PCT seems to have little impact on QoL [
12]. However, the latter study included only 12 participants with PCT, most of whom were likely in clinical remission, and those results may have limited relevance for symptomatic patients.
Previous research on photosensitive disorders has shown that, despite their diverse aetiologies, these conditions can have a high psychological impact [
24], including increased anxiety, depression, psychological distress [
25,
26], reduced psychological well-being, and impact on lifestyle [
27]. In addition, blistering diseases are associated with lower QoL, shame and the impression of poor hygiene [
28]. PCT is a treatable, non-fatal condition, but the patients should avoid sunlight when symptomatic, and susceptibility factors both in the active disease phase and when in remission. Developers of guidelines for monitoring PCT should consider the subjective aspects of the condition in addition to the therapeutic outcomes. Although we cannot draw conclusions of causality in the present study, our results show that symptomatic PCT is associated with reduced HRQoL. This suggests that appropriate follow-up, such as annual assessments, to prevent and detect relapses is important to improve patient outcomes.
Of the 61 participants, 25 reported having started treatment before answering the questionnaire. Clinical and biochemical remission may take up to 13 months [
7,
8]. Although 12 of the 25 reported having started treatment less than two months ago, and none had received treatment for more than four calendar months, we did observe a significant difference in HRQoL between those having started and those who had not started treatment (Table
2). These differences were related to bodily pain, and suggests that treatment may induce, at least from a subjective point of view, rapid improvement, as has been reported previously [
10].
Urinary porphyrin concentrations are used to diagnose and monitor disease activity in people with PCT. Most of the porphyrins in the urine of PCT patients are uroporphyrin, and we, therefore, used uroporphyrin concentration as a biochemical indicator of disease activity. PCT patients can show a keen interest in laboratory analyses and test results [
10], and it is likely that they expected their urinary concentrations to reflect the severity of symptoms. However, we found no associations between urinary uroporphyrin concentration and self-reported occurrence and localization of PCT symptoms. However, the localization of symptoms does not necessarily reflect the severity of the skin symptoms and additionally, it is likely that there may be individual thresholds for urinary uroporphyrins to trigger photosensitization, and the distribution of skin symptoms will also depend on the degree of light exposure.
We observed that men had significantly lower urinary uroporphyrin at the time of sampling compared with women (Table
2), in spite of the fact that women sought medical attention for their PCT symptoms quicker than men. We found no differences in urinary excretion between participants with familial and sporadic PCT or between any other groups (smoking, alcohol). Our observed sex difference in urinary uroporphyrin concentrations may be an incidental finding or may be related to hormonal factors, as UROD activity is influenced by oestrogen [
29]. Eight women reported oestrogens as a precipitating factor.
Women reported more PCT symptoms and lower QoL than men. Women in general are known to report lower QoL [
30] and more subjective health complaints [
31,
32]. Analysis of the associations between self-reported symptoms and HRQoL showed a strong association between symptoms and PCS in men, while this association was only moderate in women (Table
3) The association between mental aspects and HRQoL was not present in men, and only moderately in women, which is in line with the results of a previous study on illness perception in PCT, where sex was not associated with porphyria related psychological distress [
11]. Based on the data from the present study, we can therefore not draw any conclusions in regards to gender differences in the subjective experiences of PCT.
Itching was the third most reported symptom, and more than half of the participants (59%) reported this (Table
4). Itching is associated with reduced HRQoL [
33‐
36], and although previously reported [
10,
37], it is rarely included in descriptions of PCT, and physicians need to address this in this patient group. This is particularly important since itching may damage already frail skin, which can increase risk of infections and delay healing.
Limitations
We found that symptoms of PCT were associated with reduced HRQoL (Table
3). However, the cross-sectional design precludes us from drawing conclusions about causality.
Another limitation is that we did not measure the severity of symptoms on a scale, and therefore all symptoms are scored as equal in severity, which is not necessarily the case. Consequently, we do not know whether the scoring method in this study accurately reflects the patients’ perception of the severity of symptoms, and the Norwegian Porphyria Registry will evaluate this mode of measuring symptoms in the future. However, our data allow us to conclude that occurrence and localization of symptoms were associated with reduced HRQoL in these patients.
A time gap of up to six months between the time of sampling and answering the questionnaire represents a limitation of the study. However, participants were unlikely to learn about their PCT diagnosis before three to 10 weeks after the sampling date, and the median number of days from sampling to completing the questionnaire was 70 (range 21–167 days). In addition, the participants were asked about which symptoms they had experienced in connection to PCT and the SF-12 has a standard four-week recall period. Still, for some participants, recall bias might have affected their responses.
The number of non-responders is relatively high and the present study had a response rate of 55%, which is a potential problem in regard to representability. This is, however, a common problem and average response rates have been estimated to approximately 53% [
38]. We did not perform any further analyses of the non-respondents because according to our Ethical Committee, such data extraction and analyses cannot be performed without consent.
We used a generic measure of HRQoL (SF-12), but a dermatology-specific instrument may have been more appropriate. However, the SF has been recommended as a generic instrument that is well suited to dermatology, preferably in combination with the Skindex-29 [
39].
We performed multiple tests of many groups, increasing the possibility of a chance finding. Unfortunately, our sample size was too small to perform any adjustments for multiplicity. We did, however, conduct non-parametric tests to better model the small sample sizes we had per group, which have lower study power than standard tests.
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