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

Abstract

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.