Sick leave, disability, and mortality in acute hepatic porphyria: a nationwide cohort study

Background: Acute hepatic porphyria (AHP) consists of three rare metabolic disorders. We investigated the risk of long-term sick leave, disability pension, and premature death in individuals with AHP compared to the general population. Methods: In a nationwide cohort study from 1992 to 2017, records of 333 persons (total person-years = 6728) with a confirmed AHP diagnosis were linked to several national compulsory registries (reference population = 5,819,937). We conducted survival analyses to assess additional risk. Results: Persons with AHP had higher risks of accessing long-term sick leave (adjusted hazard ratio (aHR): 1.5, 95% confidence interval (CI): 1.3, 1.7) and disability pension (aHR: 1.9, CI: 1.5, 2.4). The risk was highest in persons who had been hospitalised for acute attacks, while no additional risk was observed in asymptomatic AHP gene mutation carriers. The median age when accessing disability pension was 45 years, 21 years younger than the general population. AHP was associated with increased risk of mortality due to hepatocellular carcinoma (adjusted mortality rate ratio (aMRR): 84.4, CI: 37.8, 188.2), but no overall increased risk of premature death was observed. Conclusions: Persons with symptomatic AHP were at increased risk of accessing long-term sick leave and disability pension but not of premature death.publishedVersio

The Association of Meat Intake With All-Cause Mortality and Acute Myocardial Infarction Is Age-Dependent in Patients With Stable Angina Pectoris

Background: Red and processed meat intake have been associated with increased risk of morbidity and mortality, and a restricted intake is encouraged in patients with cardiovascular disease. However, evidence on the association between total meat intake and clinical outcomes in this patient group is lacking. Objectives: To investigate the association between total meat intake and risk of all-cause mortality, acute myocardial infarction, cancer, and gastrointestinal cancer in patients with stable angina pectoris. We also investigated whether age modified these associations. Materials and Methods: This prospective cohort study consisted of 1,929 patients (80% male, mean age 62 years) with stable angina pectoris from the Western Norway B-Vitamin Intervention Trial. Dietary assessment was performed by the administration of a semi-quantitative food frequency questionnaire. Cox proportional hazards models were used to investigate the association between a relative increase in total meat intake and the outcomes of interest. Results: The association per 50 g/1,000 kcal higher intake of total meat with morbidity and mortality were generally inconclusive but indicated an increased risk of acute myocardial infarction [HR: 1.26 (95% CI: 0.98, 1.61)] and gastrointestinal cancer [1.23 (0.70, 2.16)]. However, we observed a clear effect modification by age, where total meat intake was associated with an increased risk of mortality and acute myocardial infarction among younger individuals, but an attenuation, and even reversal of the risk association with increasing age. Conclusion: Our findings support the current dietary guidelines emphasizing a restricted meat intake in cardiovascular disease patients but highlights the need for further research on the association between meat intake and health outcomes in elderly populations. Future studies should investigate different types of meat separately in other CVD-cohorts, in different age-groups, as well as in the general population.publishedVersio

Impact of COVID-19 on pregnancy-related healthcare utilisation: a prospective nationwide registry study.

OBJECTIVE: To assess the impact of COVID-19 on pregnancy-related healthcare utilisation and differences across social groups. DESIGN: Nationwide longitudinal prospective registry-based study. SETTING: Norway. PARTICIPANTS: Female residents aged 15-50 years (n=1 244 560). MAIN OUTCOME MEASURES: Pregnancy-related inpatient, outpatient and primary care healthcare utilisation before the COVID-19 pandemic (prepandemic: 1 January to 11 March 2020), during the initial lockdown (first wave: 12 March to 3 April 2020), during the summer months of low restrictions (summer period: 4 April to 31 August 2020) and during the second wave to the end of the year (second wave: 1 September to 31 December 2020). Rates were compared with the same time periods in 2019. RESULTS: There were 130 924 inpatient specialist care admissions, 266 015 outpatient specialist care consultations and 2 309 047 primary care consultations with pregnancy-related diagnostic codes during 2019 and 2020. After adjusting for time trends and cofactors, inpatient admissions were reduced by 9% (adjusted incidence rate ratio (aIRR)=0.91, 95% CI 0.87 to 0.95), outpatient consultations by 17% (aIRR=0.83, 95% CI 0.71 to 0.86) and primary care consultations by 10% (aIRR=0.90, 95% CI 0.89 to 0.91) during the first wave. Inpatient care remained 3%-4% below prepandemic levels throughout 2020. Reductions according to education, income and immigrant background were also observed. Notably, women born in Asia, Africa or Latin America had a greater reduction in inpatient (aIRR=0.87, 95% CI 0.77 to 0.97) and outpatient (aIRR 0.90, 95% CI 0.86 to 0.95) care during the first wave, compared with Norwegian-born women. We also observed that women with low education had a greater reduction in inpatient care during summer period (aIRR=0.88, 95% CI 0.83 to 0.92), compared with women with high educational attainment. CONCLUSION: Following the introduction of COVID-19 mitigation measures in Norway in March 2020, there were substantial reductions in pregnancy-related healthcare utilisation, especially during the initial lockdown and among women with an immigrant background

Subnational inequalities in years of life lost and associations with socioeconomic factors in pre-pandemic Europe, 2009–19:an ecological study

Background: Health inequalities have been associated with shorter lifespans. We aimed to investigate subnational geographical inequalities in all-cause years of life lost (YLLs) and the association between YLLs and socioeconomic factors, such as household income, risk of poverty, and educational attainment, in countries within the European Economic Area (EEA) before the COVID-19 pandemic. Methods: In this ecological study, we extracted demographic and socioeconomic data from Eurostat for 1390 small regions and 285 basic regions for 32 countries in the EEA, which was complemented by a time-trend analysis of subnational regions within the EEA. Age-standardised YLL rates per 100 000 population were estimated from 2009 to 2019 based on methods from the Global Burden of Disease study. Geographical inequalities were assessed using the Gini coefficient and slope index of inequality. Socioeconomic inequalities were assessed by investigating the association between socioeconomic factors (educational attainment, household income, and risk of poverty) and YLLs in 2019 using negative binomial mixed models. Findings: Between Jan 1, 2009, and Dec 31, 2019, YLLs lowered in almost all subnational regions. The Gini coefficient of YLLs across all EEA regions was 14·2% (95% CI 13·6–14·8) for females and 17·0% (16·3 to 17·7) for males. Relative geographical inequalities in YLLs among women were highest in the UK (Gini coefficient 11·2% [95% CI 10·1–12·3]) and among men were highest in Belgium (10·8% [9·3–12·2]). The highest YLLs were observed in subnational regions with the lowest levels of educational attainment (incident rate ratio [IRR] 1·19 [1·13–1·26] for females; 1·22 [1·16–1·28] for males), household income (1·35 [95% CI 1·19–1·53]), and the highest poverty risk (1·25 [1·18–1·34]). Interpretation: Differences in YLLs remain within, and between, EEA countries and are associated with socioeconomic factors. This evidence can assist stakeholders in addressing health inequities to improve overall disease burden within the EEA. Funding: Research Council of Norway; Development, and Innovation Fund of Hungary; Norwegian Institute of Public Medicine; and COST Action 18218 European Burden of Disease Network.</p

Subnational inequalities in years of life lost and associations with socioeconomic factors in pre-pandemic Europe, 2009–19: an ecological study

Background: Health inequalities have been associated with shorter lifespans. We aimed to investigate subnational geographical inequalities in all-cause years of life lost (YLLs) and the association between YLLs and socioeconomic factors, such as household income, risk of poverty, and educational attainment, in countries within the European Economic Area (EEA) before the COVID-19 pandemic. Methods: In this ecological study, we extracted demographic and socioeconomic data from Eurostat for 1390 small regions and 285 basic regions for 32 countries in the EEA, which was complemented by a time-trend analysis of subnational regions within the EEA. Age-standardised YLL rates per 100 000 population were estimated from 2009 to 2019 based on methods from the Global Burden of Disease study. Geographical inequalities were assessed using the Gini coefficient and slope index of inequality. Socioeconomic inequalities were assessed by investigating the association between socioeconomic factors (educational attainment, household income, and risk of poverty) and YLLs in 2019 using negative binomial mixed models. Findings: Between Jan 1, 2009, and Dec 31, 2019, YLLs lowered in almost all subnational regions. The Gini coefficient of YLLs across all EEA regions was 14·2% (95% CI 13·6–14·8) for females and 17·0% (16·3 to 17·7) for males. Relative geographical inequalities in YLLs among women were highest in the UK (Gini coefficient 11·2% [95% CI 10·1–12·3]) and among men were highest in Belgium (10·8% [9·3–12·2]). The highest YLLs were observed in subnational regions with the lowest levels of educational attainment (incident rate ratio [IRR] 1·19 [1·13–1·26] for females; 1·22 [1·16–1·28] for males), household income (1·35 [95% CI 1·19–1·53]), and the highest poverty risk (1·25 [1·18–1·34]). Interpretation: Differences in YLLs remain within, and between, EEA countries and are associated with socioeconomic factors. This evidence can assist stakeholders in addressing health inequities to improve overall disease burden within the EEA. Funding: Research Council of Norway; Development, and Innovation Fund of Hungary; Norwegian Institute of Public Medicine; and COST Action 18218 European Burden of Disease Network

Changes in life expectancy and disease burden in Norway, 1990–2019: an analysis of the Global Burden of Disease Study 2019

Bill & Melinda Gates FoundationpublishedVersio

Clinical long-term consequences of acute hepatic porphyria and porphyria cutanea tarda

Background: The porphyrias comprise of several rare metabolic disorders in which a crucial enzymatic step in the biosynthesis of haem is affected, mostly due to a genetic defect. The current project focused on two major disease groups of the porphyrias; acute hepatic porphyria (AHP) and porphyria cutanea tarda (PCT). AHP presents clinically as neurovisceral acute attacks, usually in adulthood, usually requiring inpatient care. Only a small proportion of AHP gene mutation carriers develop symptoms and repeat attacks are common in a minimal, mostly female subtype. It has been proposed that the precursors of haem, which are characteristically overproduced in symptomatic AHP, and to a lesser extent genetically predisposed gene carriers, may be carcinogenic. Indeed AHP is associated with an increased risk of hepatocellular carcinoma (HCC), although the magnitude of this risk remains unclear and it is uncertain if AHP increases risk of other malignancies. The acute attacks and/or chronic symptoms of AHP may also affect daily living and put patients at risk of sick leave absences and disability pension. In addition to HCC, AHP is associated with other long-term complications, such as kidney failure and hypertension, which may lead to premature death. PCT presents clinically in the form of photosensitivity, blistering, crusts and fragile skin, as a result of abnormal quantities of porphyrins in the skin. Liver damage and iron overload are common in PCT. PCT is also strongly associated with the hepatitis C virus (HCV) infection, abuse of alcohol, hemochromatosis and the use of oestrogens. Consequently, PCT may be associated with premature mortality. PCT may also be a risk factor for HCC and other cancers, but the evidence is unclear. Aims: The current project aimed to investigate the long-term consequences of AHP and PCT. Specifically, we aimed to investigate the risk of malignancies, with a particular interest in the risk of HCC. We also aimed to investigate the risk of premature death, both overall and disease-specific mortality. Finally, we investigated morbidity in persons with AHP and if there was an increased risk of long-term sick leave and/or disability pension compared to the general population. Methods: We conducted three nationwide, registry-based cohort studies. Several compulsory data sources were record linked to the Norwegian Porphyria Registry, originally in 2012 and again in 2018. All Norwegian adult residents comprising of over 5 million persons comprised the reference populations. Study I investigated cancer risk in AHP from 2000 to 2011. Study II investigated cancer and mortality risk in persons with PCT from 2000 to 2016 and study III investigated long-term sick leave, disability leave and mortality in persons with AHP from 1992 to 2017, 1992 to 2016 and 1996 to 2017, respectively. The absolute risk was assessed by calculating annual incidence, and we conducted survival analysis using several regression techniques to compare risk between persons with AHP/PCT and the reference population, adjusting for age, sex and educational attainment. We also calculated risk stratified by subtypes of AHP and PCT, namely between persons with symptomatic disease, at some point in time, and asymptomatic AHP gene carriers and between persons with sporadic and familial PCT. Sex differences in study I was investigated by a meta-analysis of several published cohort studies. Lastly, given that HCC and PCT share similar risk factors, which would confound our results, we also compared persons with PCT to persons with a history of alcohol abuse in study II. Results: We found evidence of a 108-fold (95% confidence interval (CI): 56, 207) and a 20-fold (95% CI: 8.8, 44.0) increased risk of HCC in persons with AHP and PCT, respectively. The risk was higher for women than men with AHP according to the findings of the meta-analysis in study I. The risk remained, although to a much smaller extent when comparing the risk of HCC in persons with PCT to persons with a history of alcohol abuse/dependence in study II. We also found evidence that AHP may be associated with a small increased risk of kidney and endometrial cancers and PCT associated with an increased risk of gallbladder and biliary tract cancer. A 1.5-fold increased overall risk of premature death was observed in individuals with PCT in study II, whereas a sensitivity analysis suggested that there was no increased risk of premature death in persons with AHP in study III, despite an increased risk of mortality due to HCC. Lastly, in study III, persons with AHP had a 1.5-fold increased risk of long-term sick leave (95% CI 1.3, 1.7) and a 1.9-fold increased risk of disability pension (95% CI 1.5, 2.4). The risk was even greater in persons with symptomatic AHP, but not elevated for asymptomatic AHP gene carriers. Conclusions: Persons with PCT and AHP are at substantially increased risk of HCC compared to the general population. Although lifestyle factors likely contribute to these observations in persons with PCT, something specific about PCT itself may contribute to the pathophysiology of HCC. For persons with AHP, who do not generally differ from the general population concerning HCC risk factors, our study supports previous findings that PLC is a serious life-threatening long-term consequence of AHP, and supports the idea that persons 50 years or older from this group would benefit from selective surveillance. Morbidity due to AHP also appears to result in more long-term sick leave absences from work and disability pension in persons with symptomatic AHP. Early diagnosis, counselling about precipitating factors and routine follow-up of symptomatic AHP gene carriers is, therefore, recommended

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

Porphyria cutanea tarda increases risk of hepatocellular carcinoma and premature death: A nationwide cohort study

Background Porphyria cutanea tarda (PCT) is a skin disorder originating from a deficit of the liver enzyme uroporphyrinogen decarboxylase. PCT may be a risk factor for hepatocellular carcinoma (HCC) and other cancers, but the evidence is unclear. We aimed to investigate cancer and premature mortality risk in persons with PCT. Methods The cohort study consisted of all Norwegian residents from 18 years between 2000 and 2016 (n = 5.4 million). 612 persons with PCT, and all cancer diagnoses and causes of death were identified through record linkage between national registries. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were adjusted for age, sex, education and calendar years. We additionally compared persons with PCT to persons with a history of chronic alcohol abuse (n = 30,468). Results Persons with PCT were more likely to be diagnosed with HCC [adjusted HR (aHR) = 19.7, CI = 8.8–44.0) and gallbladder and biliary tract cancer (aHR = 6.8, CI = 2.2–21.0) than the reference population. A moderate increased risk for HCC (aHR = 3.1, CI = 1.2–7.7) and gallbladder and biliary tract cancer (aHR = 4.0, CI = 1.1–14.4) remained when compared to persons with a history of chronic alcohol abuse. Additionally, compared to the reference population, persons with PCT had an increased risk of premature death (aHR = 1.5, CI = 1.2–1.7), due to the following causes of death: malignant neoplasms (aHR = 1.4, CI = 1.0–1.9), diseases of the liver (HR = 5.5, CI = 2.5–12.2), and drug and alcohol overdose (HR = 9.9, CI = 4.7–20.8). Conclusions Persons with PCT had an increased risk of HCC and cancer of the gallbladder and biliary tract, as well as premature death. Although most of our findings can likely be explained by common lifestyle risk factors, something inherent in PCT may contribute to the development of HCC

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.publishedVersio