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).
Risk of first ever LTSL and disability pension
80.9% of persons with PCT compared to 71.0% of the matched controls accessed LTSL over 211,784.8 person-years at risk under observation. The annual incidence was 10.4% for persons with PCT compared to 7.3% in matched controls, constituting a 1.4-fold increased risk (HR=1.4, CI: 1.3, 1.5) (Figure 2). Risk was greatest in persons with sporadic (HR=1.5, CI: 1.3, 1.7) and unclassified (HR=1.6, CI: 1.2, 2.2) PCT, but also increased in persons with familial PCT (HR=1.3, CI: 1.2, 2.2) (Figure 2).
37.3% of persons with PCT accessed disability pension compared to 26.6% of matched controls resulting in a 1.5-fold (HR=1.5, CI: 1.3, 1.7) increased risk (Figure 2). Within subgroups, risk was increased 1.6 (HR=1.6, CI: 1.4, 2.0) in persons with sporadic PCT, 2.1 (HR=2.1, CI: 1.5, 3.0) in persons with unclassified PCT and 1.2 (HR=1.2, CI: 0.9, 1.5) in persons with familial PCT (Figure 2).
Excess risk of LTSL increased from 1.3 pre-PCT (HR=1.3, CI: 1.1, 1.4) to 1.5 during-PCT (HR=1.5, CI: 1.1, 2.1), but then decreased post-PCT (HR=0.7, CI: 0.5, 1.1). Excess risk of disability pension also increased from 1.3 pre-PCT (HR=1.3, CI: 1.0, 1.6) to 1.5 during-PCT (HR=1.5, CI: 1.0, 2.2), and increased to 2.0 post-PCT (HR=2.0-fold, CI: 1.5, 2.6). However, overlapping CIs suggest that these differences between pre-PCT, during-PCT and post-PCT were non-significant (Supplementary Table 2).
We found no evidence that effect of PCT on LTSL differed between men and women (p-value for interaction sex#exposure = .636). There was a trend, although with considerable uncertainty, that the effect of PCT on LTSL was stronger with higher education (primary education [HR=1.3, CI: 1.1, 1.6], upper secondary school [HR=1.4, CI: 1.2, 1.6] and university education [HR=1.5, CI: 1.2, 1.8]). However, this was not a statistically significant interaction (p-value for interaction education#exposure = .420).
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 1.3 more days per year (IRR=1.3, CI=1.0, 1.5) and had 1.1 more annual episodes than matched controls (IRR=1.1, CI=1.0, 1.5) (Table 2). Excess LTSL days increased from pre-PCT (IRR=1.4, CI=1.2, 1.7) to during PCT (IRR=2.0, CI=1.4, 3.0), but were reduced post-PCT (IRR=0.30, CI=0.1, 0.5) (Table 2). Excess LTSL events decreased from pre-PCT (IRR=1.4, CI=1.2, 1.7) to during-PCT (HR=1.3, CI=0.9, 1.8), and again in post-PCT (HR=0.3, CI=0.1, 0.5) (Table 2). Overlapping CIs suggest, however, that differences between pre and during – PCT estimates for events and total days were non-significant. 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).
LTSL and disability pension causes
Compared to matched controls, LTSL risk was increased for general and unspecific symptoms in persons with familial PCT (IRR=1.4, CI=1.0, 2.0), digestive issues (IRR=2.5, CI=1.3, 4.8), and muscle and joint pain (IRR=2.1, CI=1.3, 3.3) in persons with sporadic PCT, and endocrine and metabolic disorders for both sporadic PCT (IRR=13.3, CI=9.5, 18.7), and familial PCT (IRR=15.0, CI=10.1, 22.3). Compared to matched controls, risk of disability pension in persons with PCT was increased due to malignant neoplasms (IRR=2.4, CI=1.4, 4.2), PCT (IRR=49.2, CI=38.8, 62.4), hereditary hemochromatosis (n=2, IRR=29.1, CI=10.8, 78.8), cerebrovascular diseases (n=7, IRR=3.2, CI=1.6, 6.7), 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), diseases of the skin & subcutaneous tissue (n=4, IRR=4.2, CI=1.6, 11.0), and diseases of the musculoskeletal system & connective tissue (IRR=2.5, CI=1.9, 3.2). In the subgroup analysis, risk was only increased in persons with sporadic PCT for malignant neoplasms (IRR=3.0, CI=1.4, 6.2), and neurotic and mood disorders (IRR=2.2, CI=1.2, 3.9), and increased in both persons with sporadic PCT (IRR=3.3, 2.4, 4.6) and familial PCT (IRR=1.6, CI=1.0, 2.6) for diseases of the musculoskeletal system & connective tissue. Prevalence rates and IRRs for LTSL and disability pension diagnostic codes are depicted in 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 (Supplementary Table 3). 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 (Supplementary Table 3).