Porphyria cutanea tarda in Scotland: underlying associations and treatment approaches.

BACKGROUND: Despite its rarity, porphyria cutanea tarda (PCT) is globally recognized as the most common form of cutaneous porphyria. This study aims to review the underlying associations and treatment of PCT in Scotland. METHODS: We retrospectively reviewed data on 27 patients diagnosed with PCT between 1987 and 2022 at the Scottish Cutaneous Porphyria Service. RESULTS: Males slightly predominated (66.7%). The mean ± standard deviation (SD) age at diagnosis was 55.6 ± 12.5 years. Common associated factors were heavy alcohol intake (88.5%), genetic hemochromatosis (72%), smoking (45.5%), and hepatitis C virus infection (16%). Most had multiple associated factors (70.4%). Patients with genetic hemochromatosis with the C282Y genotype exhibited higher median transferrin saturation (69.5 vs. 35, P = 0.004) and ferritin levels (observed in males only) (1175 vs. 339; P = 0.014) than those with the H636D genotype. Most (52%) received combination therapy of venesection and antimalarials, followed by venesection monotherapy (32%) and antimalarial monotherapy (16%). Overall, 95.2% achieved biochemical improvement. Median time to improvement was 7, 5, and 9 months with venesection, antimalarial, and combined treatments, respectively (P = 0.173). Biochemical remission was achieved in 50% of patients. Remission occurred in 2/4 of patients with antimalarial monotherapy (median time 19 months) and 9/13 patients with combined treatment (median time 26 months). Biochemical relapse was found in three patients, all of whom received combination therapy. CONCLUSION: Excess alcohol intake and genetic hemochromatosis were the most common underlying associations with PCT in our Scottish cohort. Treatment for PCT should be individualized, and long-term follow-up is needed to monitor for disease relapse.

Dermatological Manifestations in Patients With Chronic Kidney Disease: A Review.

Chronic kidney disease (CKD) is a progressive disease and has multiple clinical manifestations; when CKD reaches the end stage, at least one cutaneous manifestation appears due to some increased toxin levels or a constant proinflammatory state. Nonspecific manifestations include pruritus, xerosis, pigmentation disorders, acquired ichthyosis, purpuric spots, and nail disorders. Some specific manifestations are bullous dermatoses, acquired perforating dermatoses (APD), eruptive xanthoma, access site infections, calcifying disorders, and nephrogenic systemic fibrosis (NSF). All these cutaneous changes negatively impact patients; early recognition and diagnosis of these dermatoses will make a difference in their quality of treatment. Exploring a patient's skin is fundamental to suspect some diseases and increased toxin levels; pruritus occurs when uremic toxins are raised, and nail disorders are associated with hypoalbuminemia. This review provides the clinician with information on the clinical manifestations that occur in CKD, including epidemiology, pathophysiology, clinical manifestations, diagnosis, histopathology, treatment, and life impact of the dermatoses in CKD.

Update on the Porphyrias.

The porphyrias are a group of rare diseases, each resulting from a defect in a different enzymatic step of the heme biosynthetic pathway. They can be broadly divided into two categories, hepatic and erythropoietic porphyrias, depending on the primary site of accumulation of heme intermediates. These disorders are multisystemic with variable symptoms that can be encountered by physicians in any specialty. Here, we review the porphyrias and describe their clinical presentation, diagnosis, and management. We discuss novel therapies that are approved or in development. Early diagnosis is key for the appropriate management and prevention of long-term complications in these rare disorders.

Acute Porphyria: An Unusual Case Of Quadriparesis, Hypertension, Recurrent Severe Cyclic Abdominal Pain, And Seizures.

Porphyria refers to a rare group of genetically inherited or acquired disorders that arise due to reduced metabolic activity of any of the enzymes in the haem biosynthetic pathway. Defect in any enzyme causes the presentation of symptoms of porphyria. The epidemiology of Acute Intermittent Porphyria (AIP) is complicated because of its rarity and delay in diagnosis. We present the case of a seven-year-old girl who presented with multisystem involvement; her symptoms were quadriparesis, hypertension, recurrent severe cyclic abdominal pain, and seizures. These symptoms together were not explained by the differentials taken into account. She presented before puberty with no family history of such conditions, while being born of consanguineous marriage. Her symptoms along with urinary porphobilinogen positivity test helped to reach the diagnosis of AIP in the absence of cutaneous manifestations. This case highlights the variable presentation of porphyria and emphasises the importance of appropriate and timely diagnosis and management in these patients.

Porfiria cutánea tarda que simula esclerosis sistémica progresiva / Porphyria cutanea tarda mimicking progressive systemic sclerosis

Resumen Los síndromes esclerodermiformes suelen imitar muy bien una esclerosis sistémica progresiva, y es la presencia de ampollas cutáneas en áreas fotoexpuestas con hiperpigmentación los datos diferenciales para diagnosticar una porfiria. Presentamos el caso de un varón de 48 años con fotosensibilidad, fragilidad capilar, ampollas cutáneas e hiperpigmentación asociado a esclerodactilia, con pérdida cicatrizal distal de tejido en los dedos de las manos, que simuló a la perfección una esclerosis sistémica progresiva. La analítica mostró negatividad para anticuerpos antinucleares, antitopoisomerasa y anticentrómero, con valores altos de uroporfirinas en orina. El tratamiento con flebotomías e hidroxicloquina mejoró la fotosensibilidad y la fragilidad cutánea.

Abstract Sclerodermiform syndromes usually mimic progressive systemic sclerosis very well, with the presence of skin blisters in photo-exposed areas with hyperpigmentation being the differential data for diagnosing porphyria. We present the case of a 48-year old man with photosensitivity, capillary fragility, skin blisters, and hyperpigmentation associated with sclerodactyly with distal scar tissue loss on the fingers, which perfectly simulated progressive systemic sclerosis. The analysis showed negativity for antinuclear, antitopoisomerase and anticentromere antibodies, with high levels of uroporphyrins in urine. Phlebotomy and hydroxycloquine treatment improved photosensitivity and skin fragility.

A Rare Case of Hereditary Hemochromatosis Presenting With Porphyria Cutanea Tarda.

Hereditary hemochromatosis is an autosomal recessive condition with incomplete penetrance that is most commonly caused by a mutation in the HFE gene. Hereditary hemochromatosis can remain asymptomatic in some patients until triggered by certain events. Porphyria cutanea tarda is a condition that can lead to iron overload due to defective synthesis of heme and can cause the onset of adult-onset hereditary hemochromatosis. Herein, we present a case where a 77-year-old man presented with painful blisters on the sun-exposed areas of his hands and was diagnosed with porphyria cutanea tarda. Further testing for mutations in the HFE gene given elevated ferritin was performed and returned positive, which confirmed the diagnosis of adult-onset hereditary hemochromatosis. The patient received serial therapeutic phlebotomy for iron overload and adopted lifestyle modifications such as avoiding sun exposure of upper extremities. The patient's blisters and laboratory iron panel parameters improved with continued phlebotomy. Therapeutic phlebotomy has been demonstrated to be an effective first-line therapy in patients with dual diagnosis. Our case highlights that cutaneous symptoms due to porphyria cutanea tarda may be the first presenting symptom in patients with underlying hemochromatosis.

Relación estructura-función de la enzima uroporfirinógeno descarboxilasa: implicancias para la comprensión y el tratamiento de la porfiria cutánea tarda / Structure-function relationship of the enzyme uroporphyrinogen decarboxylase: implications for the understanding and treatment of porphyria cutanea tarda / Relação estrutura-função da enzima uroporfirinogênio descarbioxilase: implicações para a compreensão e tratamento da porfiria cutânea tardia / Reconocimiento a la trayectoria del Prof. Dr. Juan Miguel Castagnino†

Resumen La uroporfirinógeno descarboxilasa humana (UROD-h) es la quinta enzima del camino biosintético del hemo y su actividad deficiente, relacionada a mutaciones en su gen, se encuentra asociada a un subgrupo de porfirias. El objetivo de este trabajo fue estudiar la relación entre la dimerización de la enzima y su actividad enzimática y comprobar si la dimerización de UROD-h es imprescindible tanto para la primera etapa de la reacción (urogen→heptagen), como para la segunda etapa (heptagen→coprogen). Con ese objetivo, se expresó y purificó la UROD-h hasta homogeneidad, se analizó el comportamiento dímero-monómero bajo distintas condiciones que pudieran desplazar el equilibrio de dimerización y se evaluó la actividad enzimática en dichas condiciones. Los resultados obtenidos sugieren que la especie activa para la primera etapa de la reacción es el homodímero y que tanto el dímero como el monómero se comportan como especies activas para la segunda etapa de la reacción. Se propone que mutaciones clínicas como la Y311C, existentes en pacientes con porfiria cutánea tarda, podrían afectar la estabilidad del dímero y podrían ser el blanco para futuras terapias génicas.

Abstract Human uroporphyrinogen decarboxylase (UROD-h) is the fifth enzyme in the heme biosynthetic pathway and its deficient activity, related to mutations in its gene, is associated with a subset of porphyrias. The objective of this work was to study the relationship between the dimerisation of the enzyme and its enzymatic activity and to verify if the dimerisation of UROD-h is essential both for the first stage of the reaction (urogen→heptagen), and for the second stage (heptagen→ coprogen). With this objective, the UROD-h was expressed and purified to homogeneity, the dimer- monomer behaviour was analysed under different conditions, which could shift the dimerisation equilibrium, and the enzymatic activity was evaluated under these conditions. The results obtained suggest that the active species for the first stage of the reaction is the homodimer, and both the dimer and the monomer behaved as active species for the second stage of the reaction. It is proposed that clinical mutations such as Y311C, existing in porphyria cutanea tarda patients, could affect dimer stability and could be the target of future gene therapies.

Resumo A enzima uroporfirinogênio descarboxilase humana (UROD-h) é a quinta enzima da via biossintética do heme e sua atividade deficiente, relacionada com mutações em seu gene, está associada a um subgrupo de porfirias. O objetivo deste trabalho foi estudar a relação entre a dimerização da enzima e sua atividade enzimática e comprovar se a dimerização da UROD-h é imprescindível tanto para a primeira etapa da reação (urogênio→heptagênio), quanto para a segunda etapa (heptagênio→coprogênio). Com esse objetivo, a UROD-h foi expressa e purificada até a homogeneidade, o comportamento de dímero-monômero foi analisado sob diversas condições, que puderam deslocar o equilíbrio de dimerização, e a atividade enzimática foi avaliada em tais condições. Os resultados obtidos sugerem que a espécie ativa para a primeira etapa da reação é o homodímero, e tanto o dímero quanto o monômero se comportam como espécies ativas para a segunda etapa da reação. Propõe-se que mutações clínicas como Y311C, existentes em pacientes com porfiria cutânea tardia, poderiam afetar a estabilidade do dímero e poderiam ser o alvo de futuras terapias gênicas em porfiria cutânea tardia.

Iron Metabolism in the Disorders of Heme Biosynthesis.

Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme-the iron-chelated form of protoporphyrin IX-is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.

Renal Transplantation Could Reverse Dialysis-Associated Porphyria.

Pseudoporphyria (PP) is a relatively infrequent, photodistributed bullous dermatosis that clinically, histopathologically, and immunologically resembles porphyria cutanea tarda (PCT), but is not accompanied by porphyrin abnormalities in the serum, urine, or stool. It was initially described in patients with renal failure on dialysis as 'bullous dermatosis of hemodialysis.' Pseudoporphyria has been seen in patients with end-stage renal disease on hemodialysis. No treatment has proved efficacious in the management of pseudoporphyria. However, N-acetylcysteine has been anecdotally reported to be effective in the management of hemodialysis-related pseudoporphyria and other porphyric diseases. Our patient had developed multiple skin lesions all over the body when hemodialysis started. The lesions were erythematous with fluid-filled vesicles, and bullae with cutaneous fragility that were evaluated and diagnosed as pseudoporphyria. The patient was treated with available all medication in the literature but was not relieved. However, all skin lesions completely healed within 22 days post renal transplantation. Renal transplantation proved to be the cure for dialysis-induced pseudoporphyria resistant to conventional drug therapy.

Skin Changes in Cirrhosis.

Skin manifestations of systemic disorders give a clue to the organ involved and help identify the possible disease-causing injury. Skin changes of liver cirrhosis are not specific, as they may be seen in disorders not involving the liver. Thus, a constellation of skin changes along with systemic features may help us to identify the disease-causing liver cirrhosis. Pruritus is one of the most common and distressful symptoms of liver cirrhosis, severely affecting the quality of life, which further necessitates understanding cutaneous manifestations of cirrhosis. Other nonspecific cutaneous manifestations include spider telangiectasia, palmar erythema, paper money skin, xanthomas, pigmentation changes, nutritional deficiencies, hair changes, and nail changes. This review discusses the nonspecific skin manifestations associated with liver cirrhosis followed by specific cutaneous findings seen in common diseases causing liver cirrhosis, such as viral infections, biliary tract disorders, chronic alcoholism, and metabolic disorders. Early recognition of cutaneous features can help prevent or delay the development of complications and end-stage disease, decreasing morbidity and mortality.

Risk of Hepatocellular Carcinoma in Patients with Porphyria: A Systematic Review.

Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy. Porphyrias are inborn defects in the heme biosynthesis pathway resulting in neurovisceral manifestations and cutaneous photosensitivity attacks with multi-systemic involvement. Its estimated prevalence nears 5 per 100,000 patients worldwide. Subclinical liver disease is common, which can progress into transaminitis, fibrosis, cirrhosis, and malignancy. However, data on the incidence of primary liver cancer are lacking. We aim to determine the risk of hepatocellular carcinoma (HCC) in patients with porphyria. A systematic review and pooled analysis were conducted through 2021 on studies assessing blood tests, imaging, cancer development, liver transplant, surgical resection, and outcomes in porphyria. In total, 19 studies, which included 7381 patients with porphyria (3476 females), were considered for the final review. In eight studies, alpha-fetoprotein levels were elevated between 200 and 1000 IU/mL. Of the total cohort of patients with porphyria, primary liver cancer was diagnosed in 351 patients (4.8%), of whom 243 (3.3% of the total) were found to have HCC. A subset of patients was found to have cholangiocarcinoma (n = 18; 0.3% of the total). Interestingly, advanced liver disease or cirrhosis was not a prerequisite for the formation of HCC in a small group of patients. Of the total cohort, 30 patients underwent liver resection, 48 patients underwent liver transplantation, and 327 patients died. Patients with porphyria are at risk of developing primary liver malignancy. Further studies should aim to develop diagnostic and prognostic models aimed at the early detection of HCC in porphyria.

Between a rock and a hard place: management of systemic lupus erythematosus and porphyria cutanea tarda.

Porphyria cutanea tarda (PCT), the most common porphyria, is a rare photodermatosis characterized by fragile, hemorrhagic bullae and erosions with associated milia, hyperpigmentation, and hypertrichosis. SLE is a systemic connective tissue disease with approximately 80% of those affected manifesting cutaneous findings. These include malar and discoid rashes, photosensitivity, bullae, oral ulcerations, as well as a variety of other nonspecific findings. In this case, we illustrate a rare but established association between these two pathologic entities, and the resulting therapeutic challenge in treating a patient with both conditions. The concurrence of these two diseases poses therapeutic challenges with a paucity of evidence-based recommendations. Management with low dose weekly antimalarial therapy may be the appropriate middle ground in effectively treating the two co-morbid conditions especially in a patient with other underlying systemic conditions.

Porphyria cutanea tarda treated with short-term high-dose hydroxychloroquine: a case report.

Background: Porphyria cutanea tarda (PCT) is a kind of porphyria, which is a rare metabolic disorder with skin damage as a manifestation. The disease is mainly caused by an inherited or acquired deficiency of uroporphyrinogen decarboxylase, the fifth enzyme in heme synthesis. It is manifested primarily in patients with elevated skin fragility and greater sensitivity to sunlight. Case Description: We report here a 64-year-old Chinese male. After relevant tests, he was diagnosed with PCT. He was treated with a different regimen of oral higher doses of hydroxychloroquine (2×100 mg twice a day). After 2 weeks of treatment, the improvement of his symptoms was very obvious, with rapid regression of the lesions and no new ones. Importantly, the disease did not recur after discontinuation of the drug. Conclusions: In this case, we believe that short-term oral high-dose hydroxychloroquine can lead to rapid remission in patients with PCT. On the one hand, this treatment option reduces the economic and time costs of treating PCT compared to previous treatment options. On the other hand, a significant treatment effect in a short period of time can motivate the patient to be more aggressive in his treatment. Therefore, this short-term oral high-dose hydroxychloroquine regimen may be a better option for the treatment of PCT.

Evolution of HCV associated porphyria cutanea tarda after HCV sustained virologic response by direct acting antivirals / Evolución de la porfiria cutánea tarda asociada al VHC tras obtenerse respuesta virológica sostenida del VHC mediante el uso de antivirales de acción directa

Objectives: Porphyria cutanea tarda (PCT) is common and usually associated with HCV chronic infection and HFE polymorphisms. Since DAA IFN-free regimens availability, SVR for HCV is nearly a constant and we wonder whether HCV SVR determine PCT evolution.Methods: Retrospective observational study including patients with HCV associated PCT from the Gastroenterology and Infectious Diseases Departments at our Hospital, treated with DAA (Apr/2015–Apr/2017). Clinical variables of PCT were collected at PCT diagnosis, after PCT treatment, before DAA use and after SVR achievement. UROD activity and C282Y/H63D polymorphisms were registered. SPSS 22.0.Results: 13 HCV-PCT patients included: median age 52.5 years; 4 females; 8 HCV/HIV co-infected (all on undetectable viral load). Classical PCT factors: 12 smoked, 9 alcohol abuse, 6 former IDU. 10 type I PCT and 1 type II PCT. HFE polymorphism: 2 cases with C282Y/H63D; H63D polymorphism in 8. PCT manifestations resolved with PCT treatment in 4 patients, almost completely in 7 patients, 1 patient referred stabilization and one worsened. After DAA treatment all the residual lesions resolved, what always led to specific treatment interruption.Conclusions: Our series of cases of HCV-associated PCT shows that SVR after DAA treatment leads to PCT resolution. Porphyrin levels are not needed after ending PCT specific treatment interruption when there are no residual skin lesions in HCV-associated PCT.(AU)

Objetivos: La porfiria cutánea tarda (PCT) es un trastorno frecuentemente asociado con la infección por VHC y los polimorfismos HFE. Desde la aparición de los AAD en regímenes libres de IFN, la RVS para el VHC es casi universal. Nos preguntamos si la RVS del VHC determina la evolución de la PCT asociada al VHC.Métodos: Estudio observacional retrospectivo con pacientes con PCT asociada al VHC atendidos en Gastroenterología y Enfermedades Infecciosas en nuestro centro, tratados con AAD (abril 2015 - abril 2017). Se registra información relacionada con la PCT en el momento del diagnóstico, tras iniciar tratamiento para la PCT, antes de AAD y tras RVS. Analizamos la actividad UROD y los polimorfismos C282Y/H63D. SPSS 22.0.Resultados: Se incluyen 13 pacientes con PCT asociada al VHC: edad mediana 52,5 años; 4 mujeres; 8 coinfectados VHC/VIH (todos con VIH indetectable). Factores asociados a PCT: 12 fumadores, 9 alcohol, 6 ADVP. Hubo 10 PCT clasificadas como tipo I y una PCT tipo II. HFE: 2 casos C282Y/H63D; H63D presente en 8. Tras iniciar tratamiento clásico para PCT los síntomas se resolvieron completamente en 4 casos, casi completamente en 7, se estabilizaron en un paciente y empeoraron en un paciente. Tras la RVS con AAD desaparecieron las lesiones residuales en los pacientes que las presentaban, lo que llevó a interrumpir todos los tratamientos para la PCT.Conclusiones: Nuestra serie de casos de PCT asociada al VHC muestra que la RVS para el VHC tras AAD conduce siempre a la curación de la PCT. Según esto no sería necesaria la determinación de porfirinas tras finalizar la terapia específica para la PCT cuando no haya lesiones cutáneas residuales en la PCT asociada al VHC.(AU)

Forearm porphyrin levels evaluated by digital imaging system are increased in patients with systemic sclerosis compared with patients in pre-clinical stage.

We hypothesized that changes in skin characteristics on the forearm could be useful for early diagnosis of systemic sclerosis (SSc). We used VISIA digital imaging system to investigate this possibility for the first time. Twenty-eight Japanese patients who were diagnosed with typical or very early diagnosis of SSc (VEDOSS) were enrolled in this study, and ten age- and gender-matched patients with other disorders were included as a control group. Eight skin characteristics were analyzed. Our method of evaluating forearm skin characteristics was shown to be reproducible. The scores of WRINKLES, TEXTURE, PORES, and PORPHYRINS were higher in SSc subjects with sclerotic forearm skin (SSc forearm+; 11.004, 5.116, 3.230, and 0.084, respectively) and those without (SSc forearm-: 11.915, 4.898, 2.624, 0.0616, respectively) than in the non-SSc control subjects (10.075, 4.496, 2.459, 0.0223, respectively). Also, the scores of SPOTS, TEXTURE, PORES, UV SPOTS, BROWN SPOTS, and PORPHYRINS were elevated in SSc forearm+ (3.182, 5.116, 3.230, 5.761, 6.704, 0.084, respectively) and SSc forearm- patients (2.391, 4.898, 2.624, 9.835, 5.798, 0.0616, respectively) compared with those with VEDOSS (2.362, 4.738, 2.234, 5.999, 4.898, 0.0169, respectively). We found statistical significance in the difference in score of PORPHYRINS between SSc forearm- and VEDOSS groups (p = 0.044), and between SSc forearm+ and VEDOSS groups (p = 0.012). Therefore, they can be used to differentiate VEDOSS from early or mild SSc cases, which is sometimes clinically problematic. Our study also suggests that the porphyrin research will lead to a better understanding of SSc pathogenesis.

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.