Porphyria cutanea tarda and patterns of long-term sick leave and disability pension: a 24-year nationwide matched-cohort study

Background Porphyria cutanea tarda (PCT) is a skin disorder caused by a defect in the liver enzyme uroporphyrinogen decarboxylase and is associated with hepatitis C virus infection, high alcohol intake, smoking and iron overload. Data on the long-term morbidity of PCT is lacking. Methods We conducted a nationwide matched cohort study over a 24-year period. The study sample included 534 persons aged 18–67 years with a biochemically confirmed PCT diagnosis and a sample of 21,360 persons randomly selected from the working age population, matched on age, sex and educational attainment. We investigated if persons with sporadic and familial PCT had an increased risk of long-term sick leave (LTSL) or disability pension. We further assessed risk before (pre-PCT), during (during-PCT) and after (post-PCT) the typical period of first onset to diagnosis, treatment and remission. Results Overall, persons with PCT had a 40% increased risk (hazard ratio [HR] = 1.4, 95% confidence interval [CI] = 1.3, 1.5) of LTSL and a 50% increased risk (HR = 1.5, CI = 1.3, 1.7) of disability pension. Risk of disability pension was increased pre-PCT (HR = 1.3, CI 1.3 (1.0, 1.6), during-PCT (HR 1.5, CI 1.0, 2.2) and post-PCT (HR = 2.0, CI 1.5, 2.6). For LTSL, risk was increased pre-PCT (HR = 1.3, CI 1.1, 1.4) and during-PCT (HR = 1.5, CI 1.1, 2.1), but not post-PCT. Risk was greatest in persons with sporadic than familial PCT. Diagnostic reasons for disability pension that were increased compared to matched controls were PCT or skin disease in 11 of 199 cases (PCT: n = 7, incident rate ratios [IRR] = 49.2, CI = 38.8, 62.4; diseases of the skin and subcutaneous tissue, n = 4, IRR = 4.2, CI = 1.6, 11.0). The vast majority of diagnostic reasons for accessing disability pension were related to comorbidities, PCT susceptibility factors and more general health issues such as: malignant neoplasms (n = 12, IRR = 2.4, CI = 1.4, 4.2), substance and alcohol dependence (n = 7, IRR = 5.0, CI = 2.5, 10.1), neurotic and mood—disorders (n = 21, IRR = 1.7, CI = 1.1, 2.6), and diseases of the musculoskeletal system and connective tissue (n = 71, IRR = 2.5, CI = 1.9, 3.2). Conclusions Persons with PCT have an increased risk of LTSL and disability pension indicating significant morbidity in this patient group. Appropriate long-term follow-up and monitoring for relapses and co-morbid diseases are recommended. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02201-3.

the blood stream to the skin, where they act as photosensitisers. Symptoms arise in the form of bullae, fragile skin, hypertrichosis and hyperpigmentation in the sunexposed areas, mostly of the hands and face [2]. Symptom debut typically peaks in the 5th decade of life, but can develop earlier, and has an approximate equal sex ratio [3]. In Norway, the incidence of PCT is estimated at 1 in 100,000, with about 50% being "acquired" (sporadic PCT) and 50% associated with a mutation in UROD gene (familial PCT) [3], due to two frequently occurring mutations [3]. In most other populations, the familial form makes up 20% of cases. Although familial UROD activity is reduced by up to 50 per cent in familial PCT, exposure to exogenous factors are required for clinical disease [4] and only a small number of gene mutation carriers develop symptoms [4]. The familial and sporadic types are associated with the same types of susceptibility factors; such as hepatitis C and B virus infection, high alcohol intake, smoking, iron overload including genetic hemochromatosis and the use of oestrogens [3,[5][6][7]. Liver damage and some degree of iron overload are typically observed [8]. Treatment includes reduced exposure to sunlight, the removal of precipitating factors, reduction of iron overload by repeated venesection and/or low dose chloroquine treatment to increase the mobilization of porphyrins from the liver [9,10]. Such therapies usually result in prolonged remission in most patients, but patients are at risk for relapses and annual follow-ups are recommended [11,12]. PCT is associated with an increased risk of hepatocellular carcinoma (HCC) [13][14][15][16][17] and diabetes mellitus [18].
Norway has a social assistance programme in which the employer pays the first 16 days of sickness absence and the social insurance scheme compensates beyond this until 250 days/52 weeks. Persons thereafter may qualify for disability pension if they are unable to return to work following this period of sickness absence, if they have a reduced earning capacity of at least 50% due to illness or injury, they have attempted treatment and rehabilitation, and are aged 18-66 years. Disability pension is paid until 67 years of age when persons transfer to age-retirement pension. Early exit of the workforce due to poor health is a burden for the individual, the workplace, society and the economy [19].
Even though PCT is a hepatic disease, it is typically seen by health care professionals as a treatable skin disorder. Patients, on the other hand, may perceive their illness as chronic and systematic and that may cause a range of health problems [20]. In a previous study, we found an increased risk of premature death in persons with sporadic PCT, although not familial PCT, due mostly to liver disease and alcohol and substance abuse [17]. However, data on long-term morbidity of PCT is generally scarce and the effect of this disease on patients' working ability is little investigated. An increased rate of long-term sick leave (LTSL) and disability pension is a good indicator of ill health and decreased function within a patient population during their working years.
The aims of our study were: (1) to investigate if patients with PCT receive LTSL or disability pension due to their PCT diagnosis or PCT-associated comorbidities, (2) examine differences between patients who receive benefits or did not and, (3) to assess differences between persons with sporadic and familial PCT, and (4) to assess the morbidity of PCT and the effect of this disease on patients' lives.

Data sources
Disbursements of LTSL and disability pension were derived from the Forløpsdatabasen-Trygd Database. The database, maintained by the Norwegian Labour and Welfare Administration and administered by Statistics Norway, contains complete records regarding payment of state benefits since 1992 [21]. The primary diagnosis for the LTSL was coded according to the International Classification for Primary Care, 2nd edition (ICPC-2) for LTSL and the International Classification for Disease, 9th (ICD-9) and 10th (ICD-10) editions, from 1992-1997 and 1998 to the present, respectively. All LTSL and disability pension diagnostic codes we investigated are presented in Additional file 1: Table S1.
Porphyria diagnoses, biochemical and clinical data was derived from the Norwegian Porphyria Registry [22], which was established in 2002 and is administered by the Norwegian Porphyria Centre [23]. All individuals with overt PCT are invited to participate [24]. At the time of study the data comprised of patient-reported questionnaires and biochemical and genetic laboratory data. The registry is based on informed consent [25].
Demographic information of all Norwegian residents was derived from The National Population Register [26]. Individual-based educational attainment was derived from the National Education Database [27]. Statics Norway, producing a de-identified research database, performed precise record linkage between the individuallevel data sources in 2018.

Study design, study population and matched controls
We conducted a population based, nationwide, matched-cohort study using registry data. Data regarding the exposure (PCT diagnosis) was collected previously to-and independent of-the outcome measures (i.e., LTSL, disability pension). The study period was from January 1992 to December 2016. Of the 811 persons with a confirmed PCT diagnosis in Norway by December 2016, 631 persons participated in the current study (78%), of whom 534 were eligible (sporadic PCT, n = 228; familial PCT, n = 240, unclassified PCT, n = 66). The exclusion criteria are depicted in Fig. 1.
The reference population consisted of 4,951,586 eligible adults aged 18-67 years (i.e., working age in Norway). We compared each person with PCT to 40 randomly selected controls from the reference population, matched on exact year of birth, sex and educational attainment (no education, primary and middle school education (1-10 years of education), intermediate education (11,12,13 years of education), tertiary education (14 years or more of education), and unspecified). This resulted in 21,360 controls.
Porphyrin analyses of urine, faeces and plasma, required to establish the PCT diagnosis, were conducted at the Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital [3], using algorithms described by Badminton and colleagues [28]. Sequencing of the UROD gene was performed at the Center for Medical Genetics and Molecular Medicine at Haukeland University Hospital to establish if the patient had familial or sporadic PCT. Where DNA analysis had not been performed, participants were registered as unclassified PCT.

Statistical analyses
Annual incidence rates by person/years on study and hazard ratios, calculated using Cox proportional regression models, were used to assess if persons with PCT had an increased risk of first LTSL or disability pension. A PCT diagnosis (yes/no) or PCT-subtype (familial PCT, sporadic PCT, unclassified PCT) were the exposure variables, and first ever LTSL and disability pension (yes/ no) were the outcome variables. Age at event was the timescale and we censored for time of death and when assessing LTSL, time of disability pension. Persons were enrolled into the study in 1992 or when turning 18 years, and exited at the retirement age of 67 years, death, the event of interest, or study termination in 2016-whichever occurred first. Risk was assessed over the entire working-age, rather than after diagnosis, to better describe the life course of these patients and indirect effects of PCT related risk factors and comorbidities on the outcomes. We calculated Kaplan-Meier curves to plot increased risk over age. To investigate if persons with PCT accessed LTSL more frequently and for a longer duration, we explored differences to the matched controls regarding the count of total days and episodes of LTSL, divided by person-years. Predicted counts, incidence-rate ratios (IRRs) and 95% confidence intervals (CI) of annual LTSL days and episodes were calculated by zero-inflated negative binominal regression models with robust standard errors. The models are appropriate for over dispersed data with excess zeros (i.e., no LTSL events over follow-up) [29]. Day one of LTSL was counted from the 17th day of consecutive sick leave absences. Separate models were constructed for PCT overall and the subgroups. The proportionality assumption of the Cox models was assessed by inspecting Kaplan-Meier curves and the log(− log(survival)) versus log(time) graphs for fixed covariates, including time-dependent covariates in the model for all covariates, and tests of the non-zero slope.
No major violations were detected.
To investigate the temporal relationship between risk of LTSL and disability pension with PCT, we conducted separate Cox regression models and zero-inflated negative binominal models with robust standard errors for the time before, during and following a PCT diagnosis. This was defined accounting for likely diagnostic delay and time from diagnosis to full clinical and biochemical remission in the majority of patients. 'Pre-PCT' included all events registered prior to 2 years before the diagnosis; 'during-PCT' referred to the two immediate years prior to and following the PCT diagnosis (i.e., a 4 years period); 'post-PCT' was classified as events occurring later than 2 years after the diagnosis was established. Person-time was defined separately for the three time categories accounting for working-age range (18-67 years), study period (January 1992-December 2016), the event of interest, retirement and death, or whichever came first. When assessing risk in the period before, during and after a PCT diagnosis, the 40 controls were matched based on age in years at time of porphyria diagnosis, rather than age at study start. Sex and educational attainment were still accounted for in this matching.
The clinical and biochemical differences between persons with PCT who accessed disability pension to those who did not were assessed by Chi-square for categorical outcome variables and independent samples t-tests for continuous based outcome variables. To assess risk of specific diagnostic codes of interest for LTSL and disability pension, we calculated IRRs and CIs using Poisson regression with robust standard errors and offset for months on study. Not all disability pension events had a corresponding diagnostic code (missing data for entire population = 8.9%; missing for PCT cases = 3.4%).
We conducted a crude sensitivity analysis of the main analyses to investigate the potential effect of consent bias. The analysis included all cases known to have PCT in Norway aged between 18 and 67 years to December 2016 (n = 721). The rate of new LTSL or disability pension cases was based on the same rate observed in matched controls (i.e., assuming persons who did not consent did not vary from the population). We then calculated a crude relative risk point estimate (crude in that it does not account for person-years, censoring or differences in sex, age or educational attainment in persons who did not consent) and CIs using a subtraction method [30].
Stata&SE Version 16 for Windows was used for all statistical analyses (StataCorp Stata Statistical, Software, College Station, TX, USA).

Ethical approval
The study was approved by the Western Regional Committee for Medical and Health Research Ethics, Norway (reference number: 2012/753).

Baseline characteristics
Persons with sporadic and familial PCT did not differ from the general population in relation to sex ratio, although all PCT sub-groups were significantly older at the study start (Table 1). Persons with sporadic and unclassified PCT generally had less acquired years of formal education than persons with familial PCT or the general population ( Table 1).
We found no evidence that effect of PCT on LTSL differed between men and women (p value for interaction sex#exposure = 0.636). There was a trend, although with considerable uncertainty, that the effect of PCT

Sensitivity analysis of non-consent bias for main analyses
Including persons who did not consent with a known diagnosis of PCT in Norway (n = 187) with no additional risk of LTSL or disability as matched controls in a crude sensitivity analysis, would result in a relative risk estimate of 1.1 (CI 1.1, 1.2) for LTSL and 1.3 (CI 1.2, 1.4) for disability pension. Therefore, if persons who did not consent had, hypothetically, similar rates as matched controls, rather than persons with PCT who did consent, this would have reduced the effect sizes by 20% for LTSL and 30% for disability pension. The findings would, however, remain statistically significant.

Days on sick leave and frequency of episodes
Overall, persons with PCT were on LTSL 1.  Table 2). Overlapping CIs suggest, however, that differences between pre and during-PCT estimates for events and total days were nonsignificant. Persons with sporadic disease had an increase of annual LTSL days and events overall, pre-PCT and during-PCT. This trend was less clear in persons with familial PCT (Table 2).  Tables 3 and 4, respectively.

Characteristics of disability pension receivers
Persons who accessed disability pension were more likely to have sporadic or unclassified PCT and less likely to have familial PCT, be female, were on average 4 years older, have lower educational attainment, die over the study period, have a liver disease or Type II diabetes and report sore/fragile skin as a symptom of their PCT (Additional file 3: Table S3). On the other hand, no significant differences were observed for self-reported alcohol consumption, smoking, BMI, frequency of C282Y homozygosity, oestrogen use, other symptoms of PCT or total porphyrins or uroporphyrins (Additional file 3: Table S3).

Main findings
In a nationwide matched-cohort study with a 24-year follow-up period, we found that persons with PCT had a 1.4-fold increased risk of a LTSL event and a 1.5-fold increased risk of disability pension during their working life compared to controls. Risk of disability pension was increased 1.3-times pre-PCT, 1.5-times during-PCT and 2.0-times after-PCT. Persons with sporadic and unclassified PCT had the greatest increased risk for both LTSL and disability pension.

Contribution and interpretation
To our knowledge, no previous study has investigated the association between PCT and LTSL or disability pension, which are good indicators of morbidity during the working age of a patient group compared to the general population. We expected that PCT in itself, and independent of comorbidities, may result in increased access to LTSL during symptom onset, treatment and through to remission, and indeed our findings support this hypothesis. However, we also found that risk of disability pension was increased both before and mostly following a PCT diagnosis. Susceptibility factors of PCT include excessive alcohol intake, hepatitis B and C infection and human immunodeficiency virus, especially in persons with sporadic PCT. Therefore, our findings of an increased risk of LTSL and  Models and predicted counts based on a zero-inflated negative binominal model with robust standard errors. Day one of long-term sick leave is counted from the 17th day of consecutive sick leave absences. Sick leave days and episodeswere divided by person-years on study, either for the entire study period, 2 years or more before (pre-PCT), within 2 years (during-PCT) and more than 2 after (post-PCT)-the age at the porphyria diagnosis. Estimates include 0 counts (i.e., no sick leave episode during period of study). Persons who accessed disability pension, retired, or died before these time periods were excluded from the time at risk cases. LTSL, long-term sick leave disability pension likely reflect, in part, the role of comorbidities. In Norway, diagnostic delay is typically no longer than one to two years. So increased rates of disability pension two years or more before a diagnosis is likely due to comorbidities. This was reinforced by our finding of an effect in persons with sporadic but not familial PCT two years or more before a PCT diagnosis, given as a subgroup they generally have less comorbidities than persons with sporadic PCT. Although many persons with PCT are treated and managed successfully, a number of patients experience relapses, especially if not followed up adequately. Therefore, one explanation for the excess risk of disability pension following the typical period of remission, may be due to a subset of patients who experience ongoing relapses or for whom remission is not reached. A recent meta-analysis reported a relapse rate between 5 to 17 per 100 person-years after remission for PCT    [12]. Some patients also report diffuse long-term morbidity and a range of health problems they relate to their PCT diagnosis, despite successful treatment [20]. A report by the Norwegian Porphyria Registry found that the proportion of PCT patients who attended their annual medical check-up and fulfilled the recommended procedures was 66% in 2017 and only 53% had performed assessment of their porphyrin levels [25]. Analysis of porphyrins in urine and/or plasma is important in PCT because porphyrin concentrations indicate whether the patient is in remission or should start treatment to avoid new symptoms. Diagnostic reasons for LTSL were generally similar to matched controls, such as muscle and joint pain, anxiety and depression, and was only increased compared to controls for digestive symptoms/disorders, general and unspecific symptoms and muscle and joint pain as well as endocrine and metabolic disorders, which includes the diagnosis of PCT. This may be explained in part by PCT itself or treatment for PCT, such as digestive issues as a known side-effect of chloroquine, used for treatment of PCT or related to for example hepatitis C, iron overload or other co-morbidities. Diagnostic reasons for disability pension also included substance and alcohol dependence, further supporting the role of comorbid diseases. Persons with PCT also had an increased risk of disability pension due to malignant neoplasms and diseases of the musculoskeletal system and connective tissue. In a previous study of the same cohort, we found that PCT was also associated with risk of early death and risk of hepatocellular carcinoma and gallbladder and biliary tract cancer [17]. Only seven persons were placed on a disability pension due to their PCT itself and four persons due to diseases of the skin & subcutaneous tissue, which is likely related to their PCT.
We observed a reduced risk of LTSL after the PCT diagnosis. However, during this time-period most persons with PCT were censored from the analysis due to a very high proportion having already had a LTSL event, having transitioned to disability pension or turned 67 years of age, transitioning to an old age pension. Additionally, the small subset of persons who had never had a LTSL event before or during their PCT diagnosis may also have differed from persons with PCT in general and, for a variety of reasons, may be less inclined to take LTSL. Estimates derived after a PCT diagnosis for LTSL are, therefore, likely unreliable. It is probable that this was less of an issue for disability pension given this is a less common event which typically occurs later in life and therefore, a larger proportion of persons remained in the analysis following their PCT diagnosis.

Strengths and limitations
Strengths of the current study included the prospective nation-wide cohort design with a 24-year study followup. Data for outcomes and cofactors were drawn from national compulsory registries or administrative databases. To account in part for residual confounding we matched persons with PCT to controls of the same age, sex and educational attainment randomly selected from the entire population. We further investigated differences between persons with sporadic PCT and familial PCT as an indication of confounding by comorbidities. We further adjusted for education as a proxy of socioeconomic position and lifestyle.
The diagnosis of PCT is in most patients established in the 5th or 6th decade of life [20]. Therefore, comparing this patient group to the entire population will inevitably include comparisons to larger proportions of younger people. Even after adjusting for age in our models, this may lead to residual confounding and bias our estimates. We therefore used a ratio of 40 controls per case to ensure exact matching and sufficient statistical power for our main analyses. The controls were selected at random from the target population, reducing potential selection bias.
A limitation of the current study was that we were unable to include all persons with a PCT diagnosis across Norway. Except for persons who were deceased at the design phase of the study, participation was consent based and persons who did not participate may differ to persons who did. However, the participation rate of all known persons in Norway with a confirmed diagnosis of overt PCT was relatively high at 77.8% and we were able to investigate for potential bias by conducting a crude sensitivity analysis. In this analysis we included all known eligible persons in the main analysis and assessed the effect on risk ratios by specifying, hypothetically, that the additional members had a similar rate to matched controls. We find it reassuring that although the sensitivity analysis decreased the effect size, it did not change the overall study findings.
Another limitation of the study was the lack of some potentially important confounders at the level of the population, such as alcohol use and liver disease. We used clinical questionnaires from the Norwegian Porphyria Registry for persons with PCT, which provided some indication of differences between our sub-groups and persons with PCT who accessed disability pension compared to those who did not. However, this data did contain some missing data and is subjective, and therefore, there is some potential for information bias, especially in regards to lifestyle items. Given that confounding by lifestyle factors is likely in the current study, we also adjusted for educational attainment as a proxy of socioeconomic position and lifestyle, which was available for both cases and controls. However, despite our best efforts and use of a matched control group, residual confounding remains a potential source of bias in the current study.
Lastly, welfare systems across the world vary considerably and the rates in LTSL and disability pension in Norway are likely to be different compared to other countries. As discussed previously, Norway has a generous welfare system in which all residents who are reduced in their capacity to work due to illness or disability have, in principle, fair access to social security. In countries where such systems may be more difficult to access, illness due to PCT and comorbidities may result in a loss of employment, earlier access to age-retirement pension, or persons may have to continue working despite their morbidities. LTSL and disability leave can be considered proxy measures of morbidity in this patient group, which is likely to be similar across countries regardless of the welfare system.

Conclusion
We found that persons with PCT had an increased risk of LTSL and disability pension. The risk for LTSL was increased before and during the typical time-period from first symptom onset, through to a diagnosis, treatment and remission. Risk for disability pension was increased over the entire study period, but was greatest following the typical period of remission for a porphyria diagnosis. The risk for disability pension was generally greater for persons with sporadic PCT than familial PCT, supporting the role of comorbidities. Overall, these outcomes indicate increased morbidity amongst PCT patients and, consequently, a decreased participation in the workforce. This is likely due to a number of factors such as PCT comorbid diseases and associated precipitating factors, PCT related symptoms, treatment side-effects and relapse. This highlights the importance of providing adequate follow-up of patients for their PCT and the associated comorbidities, not only until clinical remission but following this period as well.