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

Characterisation of a common hotspot variant in acute intermittent porphyria sheds light on the mechanism of hydroxymethylbilane synthase function

Hydroxymethylbilane synthase (HMBS) is the third enzyme involved in haem biosynthesis, in which it catalyses the formation of tetrapyrrole 1-hydroxymethylbilane (HMB). In this process, HMBS binds four consecutive substrate molecules, creating the enzyme-intermediate complexes ES, ES2, ES3 and ES4. Pathogenic variants in the HMBS gene are associated with the dominantly inherited disorder acute intermittent porphyria. In this study, we have characterised the p.R26H variant to shed light on the role of Arg26 in the elongation mechanism of HMBS and to provide insights into its effect on the enzyme. With selected biophysical methods, we have been able to show that p.R26H forms a single enzyme-intermediate complex in the ES2-state. We were also able to demonstrate that the p.R26H variant results in an inactive enzyme, which is unable to produce the HMB product.publishedVersio

A survey of total IgE reference intervals reported by Scandinavian and British medical laboratories – a need for harmonisation

Objectives There appears to be marked discrepancies between total IgE reference intervals (RIs) in use by many laboratories and those recommended by published studies. The aim of this study was therefore to review total IgE RIs currently reported by Scandinavian and British laboratories and to compare these to published RIs identified by a literature review. Methods Relevant laboratories were identified by test directories provided by the national accreditation bodies in Norway, Sweden, Denmark and the UK. Total IgE RIs and their sources were acquired by accessing laboratory user handbooks or by an electronic survey. In addition a literature review of published total IgE RI studies was performed. Results From 172 accredited laboratories providing total IgE analysis, data was acquired from 122 laboratories. An adult upper reference limit between 81 to 150 kU/L was reported by 89% of these. Denmark and Sweden reported the most harmonised RIs whilst Norway and the UK exhibited the least degree of harmonisation. Published adult (n = 6) and paediatric (n = 6) RI studies reported markedly higher upper limits than those currently in use by the laboratories included in this study. There were also large variations in the number of age strata in use for paediatric RIs. Conclusion This study demonstrates large variations in currently utilised IgE RIs by Scandinavian and British accredited laboratories and most report markedly lower RIs than those recommended by recent RI publications. Many laboratories likely utilise outdated RIs and should consider critically reviewing and updating their RIs.publishedVersio

Personalized reference intervals - Statistical approaches and considerations

Under embargo until: 2022-12-13For many measurands, physicians depend on population-based reference intervals (popRI), when assessing laboratory test results. The availability of personalized reference intervals (prRI) may provide a means to improve the interpretation of laboratory test results for an individual. prRI can be calculated using estimates of biological and analytical variation and previous test results obtained in a steady-state situation. In this study, we aim to outline statistical approaches and considerations required when establishing and implementing prRI in clinical practice. Data quality assessment, including analysis for outliers and trends, is required prior to using previous test results to estimate the homeostatic set point. To calculate the prRI limits, two different statistical models based on ‘prediction intervals’ can be applied. The first model utilizes estimates of ‘within-person biological variation’ which are based on an individual’s own data. This model requires a minimum of five previous test results to generate the prRI. The second model is based on estimates of ‘within-subject biological variation’, which represents an average estimate for a population and can be found, for most measurands, in the EFLM Biological Variation Database. This model can be applied also when there are lower numbers of previous test results available. The prRI offers physicians the opportunity to improve interpretation of individuals’ test results, though studies are required to demonstrate if using prRI leads to better clinical outcomes. We recommend that both popRIs and prRIs are included in laboratory reports to aid in evaluating laboratory test results in the follow-up of patients.publishedVersio

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP.publishedVersio

Excess risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study

The porphyrias comprise a heterogeneous group of rare, primarily hereditary, metabolic diseases caused by a partial deficiency in one of the eight enzymes involved in the heme biosynthesis. Our aim was to assess whether acute or cutaneous porphyria has been associated with excess risks of adverse pregnancy outcomes. A population-based cohort study was designed by record linkage between the Norwegian Porphyria Register, covering 70% of all known porphyria patients in Norway, and the Medical Birth Registry of Norway, based on all births in Norway during 1967–2006. The risks of the adverse pregnancy outcomes preeclampsia, delivery by caesarean section, low birth weight, premature delivery, small for gestational age (SGA), perinatal death, and congenital malformations were compared between porphyric mothers and the rest of the population. The 200 mothers with porphyria had 398 singletons during the study period, whereas the 1,100,391 mothers without porphyria had 2,275,317 singletons. First-time mothers with active acute porphyria had an excess risk of perinatal death [adjusted odds ratio (OR) 4.9, 95% confidence interval (CI) 1.5–16.0], as did mothers with the hereditable form of porphyria cutanea tarda (PCT) (3.0, 1.2–7.7). Sporadic PCT was associated with an excess risk of SGA [adjusted relative risk (RR) 2.0, 1.2–3.4], and for first-time mothers, low birth weight (adjusted OR 3.4, 1.2–10.0) and premature delivery (3.5, 1.2–10.5) in addition. The findings suggest women with porphyria should be monitored closely during pregnancy

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

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

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