Acute intermittent porphyria: Long-term follow up of 35 patients

array:24 ["pii" => "S238702061600108X" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.02.043" "estado" => "S300" "fechaPublicacion" => "2015-10-21" "aid" => "3076" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2014" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2015;145:332-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2 "HTML" => 2 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0025775314005739" "issn" => "00257753" "doi" => "10.1016/j.medcli.2014.06.012" "estado" => "S300" "fechaPublicacion" => "2015-10-21" "aid" => "3076" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2015;145:332-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 47 "formatos" => array:2 [ "HTML" => 28 "PDF" => 19 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original" "titulo" => "Porfiria aguda intermitente: seguimiento a largo término de 35 pacientes" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "332" "paginaFinal" => "337" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Acute intermittent porphyria: Long-term follow up of 35 patients" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figura 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1424 "Ancho" => 1576 "Tamanyo" => 133211 ] ] "descripcion" => array:1 [ "es" => "Evolución a largo término de la concentración de porfobilinógeno (PBG) y ácido delta-aminolevulínico (ALA) en un paciente del grupo B, durante el período de tratamiento con hemina (1-8 años) y después de suspender este tratamiento (8-10 años). Concentración de PBG y ALA expresada en mmol/mol de creatinina." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Carmen Herrero, Celia Badenas, Paula Aguilera, Jordi To-Figueras" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Carmen" "apellidos" => "Herrero" ] 1 => array:2 [ "nombre" => "Celia" "apellidos" => "Badenas" ] 2 => array:2 [ "nombre" => "Paula" "apellidos" => "Aguilera" ] 3 => array:2 [ "nombre" => "Jordi" "apellidos" => "To-Figueras" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S238702061600108X" "doi" => "10.1016/j.medcle.2016.02.043" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702061600108X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775314005739?idApp=UINPBA00004N" "url" => "/00257753/0000014500000008/v1_201509220049/S0025775314005739/v1_201509220049/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020616001182" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.02.053" "estado" => "S300" "fechaPublicacion" => "2015-10-21" "aid" => "3233" "copyright" => "Elsevier España, S.L.U." "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2015;145:338-40" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2 "HTML" => 2 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Brief report" "titulo" => "Occupational semicircular lipoatrophy associated with serum adipokine abnormalities" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "338" "paginaFinal" => "340" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Lipoatrofia semicircular de etiología laboral asociada a alteraciones séricas de adipocinas" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luis Reinoso-Barbero, Ramón Díaz-Garrido, María-Fernanda González-Gómez, José Olarrea, Félix Gómez-Gallego, Fernando Bandrés" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Luis" "apellidos" => "Reinoso-Barbero" ] 1 => array:2 [ "nombre" => "Ramón" "apellidos" => "Díaz-Garrido" ] 2 => array:2 [ "nombre" => "María-Fernanda" "apellidos" => "González-Gómez" ] 3 => array:2 [ "nombre" => "José" "apellidos" => "Olarrea" ] 4 => array:2 [ "nombre" => "Félix" "apellidos" => "Gómez-Gallego" ] 5 => array:2 [ "nombre" => "Fernando" "apellidos" => "Bandrés" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S002577531500072X" "doi" => "10.1016/j.medcli.2014.12.024" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577531500072X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616001182?idApp=UINPBA00004N" "url" => "/23870206/0000014500000008/v1_201604030058/S2387020616001182/v1_201604030058/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020616001108" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.02.045" "estado" => "S300" "fechaPublicacion" => "2015-10-21" "aid" => "3122" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2015;145:327-31" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 4 "HTML" => 4 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Amyloidosis complicating spondyloarthropathies: Study of 15 cases" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "327" "paginaFinal" => "331" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Amiloidosis secundaria a espondiloartritis: estudio de 15 casos" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Samantha Rodríguez-Muguruza, Melania Martínez-Morillo, Susana Holgado, Xavier Saenz-Sarda, Lourdes Mateo, Xavier Tena, Alejandro Olivé" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Samantha" "apellidos" => "Rodríguez-Muguruza" ] 1 => array:2 [ "nombre" => "Melania" "apellidos" => "Martínez-Morillo" ] 2 => array:2 [ "nombre" => "Susana" "apellidos" => "Holgado" ] 3 => array:2 [ "nombre" => "Xavier" "apellidos" => "Saenz-Sarda" ] 4 => array:2 [ "nombre" => "Lourdes" "apellidos" => "Mateo" ] 5 => array:2 [ "nombre" => "Xavier" "apellidos" => "Tena" ] 6 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Olivé" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775314006964" "doi" => "10.1016/j.medcli.2014.06.019" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775314006964?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616001108?idApp=UINPBA00004N" "url" => "/23870206/0000014500000008/v1_201604030058/S2387020616001108/v1_201604030058/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Acute intermittent porphyria: Long-term follow up of 35 patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "332" "paginaFinal" => "337" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Carmen Herrero, Celia Badenas, Paula Aguilera, Jordi To-Figueras" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Carmen" "apellidos" => "Herrero" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 1 => array:3 [ "nombre" => "Celia" "apellidos" => "Badenas" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Paula" "apellidos" => "Aguilera" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:4 [ "nombre" => "Jordi" "apellidos" => "To-Figueras" "email" => array:1 [ 0 => "JTO@clinic.ub.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Unidad de Porfirias, Grupo de Enfermedades Minoritarias del Adulto, Hospital Clinic, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servei de Dermatologia, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Porfiria aguda intermitente: seguimiento a largo término de 35 pacientes" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1205 "Ancho" => 1635 "Tamanyo" => 206108 ] ] "descripcion" => array:1 [ "en" => "Long-term progression of urinary concentration of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) in one patient in group B, under maintenance treatment with hemin. PBG and ALA concentration expressed in mmol/mol creatinine." ] ] ] "textoCompleto" => "IntroductionAcute intermittent porphyria (AIP) is a disease caused by a defect in the enzyme porphobilinogen deaminase (PBGD; also called hydroxymethylbilane synthetase, EC 2.5.1.61), which catalyses the third step of heme synthesis.<a class="elsevierStyleCrossRef" href="#bib0085">1</a> The enzyme deficiency results from the existence of mutations in the PBGD gene located at chromosomal region 11q24.1 and consisting of 15 exons.<a class="elsevierStyleCrossRef" href="#bib0090">2</a> The disease is transmitted in an autosomal dominant way with a low clinical penetrance, although, so far, this has not been accurately estimated.The annual incidence of new cases in most European countries has been estimated at 0.13 per million inhabitants, except in Sweden, which has a higher incidence due to founder effects and genetic migration.<a class="elsevierStyleCrossRef" href="#bib0095">3</a> Subjects who carry the genetic defect have potential risk of very severe acute neurovisceral attacks. This is much more common in women than in men, and never happens before puberty.<a class="elsevierStyleCrossRefs" href="#bib0100">4,5</a>In its active mode, AIP is in the form of an acute dysfunction of the central nervous system (CNS), autonomic and peripheral (PNS).<a class="elsevierStyleCrossRef" href="#bib0110">6</a> Patients come to the emergency room with acute abdominal pain, tachycardia, hypertension, seizures, psychiatric disorders, and hyponatremia. PNS involvement can induce motor neuropathy, which can cause tetraparesia and even respiratory paralysis. The clinical features are associated with a sharp hepatic overproduction of heme precursors, porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) after induction of the ALA synthetase 1 (ALAS1) gene. According to the most plausible pathophysiological explanation, ALA hepatic export and the resulting cellular toxicity could be the cause of neurological crises.<a class="elsevierStyleCrossRef" href="#bib0115">7</a>The acute attacks result from the concomitance of the genetic/enzymatic underlying defect and hormonal or other precipitating factors (hypocaloric diet, stress, drug administration, infections, etc.) that can induce expression of the ALAS1 gene in the liver.<a class="elsevierStyleCrossRef" href="#bib0115">7</a> The abrupt induction of the first part of the metabolic pathway, coupled with liver PBGD underactivity, results in PBG and ALA accumulation. The ALAS1 gene is partly controlled by a heme negative feedback mechanism, last product of the metabolic pathway.<a class="elsevierStyleCrossRef" href="#bib0090">2</a> In case of acute attack, the intravenous administration of hemin (human hemin stabilized with arginine, Normosang®), which restores the hepatic heme reserve and reduces ALAS1 induction is a measure of high therapeutic effectiveness that, in most cases, resolves neurovisceral crises, although not allowing a complete biochemical remission.<a class="elsevierStyleCrossRef" href="#bib0105">5</a> The administration of glucose also has an inhibitor ALAS1<a class="elsevierStyleCrossRef" href="#bib0090">2</a> effect (though less effective).A minority of patients with AIP experience recurrent attacks requiring repeated heme administration for long periods of time. Liver transplantation has taken place in some very severe recurrent cases. In these cases, the transplant has cured the disease, thus demonstrating its hepatic origin.<a class="elsevierStyleCrossRef" href="#bib0120">8</a>Our study is the summary of the experience (expanded over several decades) in the diagnosis, treatment and research of the AIP in the Porphyria's Unit (Department of Dermatology and Biomedical Diagnostic Centre) of the Hospital Clínic of Barcelona. All the cases treated in this unit between 1993 and 2013 are presented herein, together with a description of their clinical and biochemical characteristics. The prevalence of the disease in our country has been estimated, as well as a list of precipitating factors and a progression categorization of recurrent cases.Patients and methodDemographic, clinical, biochemical and family data of all patients with AIP who were treated consecutively by the Porphyria's Unit of the Hospital Clínic of Barcelona between the years 1993 and 2013 were collected. During this period, 35 patients were treated and 94 relatives were studied.AIP diagnosis in patients was made according to the criteria agreed by the European Porphyria Initiative.<a class="elsevierStyleCrossRef" href="#bib0125">9</a> These criteria include: characteristic clinical symptoms, significant PBG, ALA and urine porphyrins increase, fluorescence emission peak in plasma, porphyrins and isomers high-performance liquid chromatography in stool, decreased PBGD enzyme activity in red blood cells and, finally, confirmation by PBGD gene mutation detection.<a class="elsevierStyleCrossRef" href="#bib0130">10</a>The classification criteria in clinically asymptomatic relatives had to do with the presence of PBGD gene mutation and a low activity in the PBGD enzyme in blood.Results35 new patients were identified with AIP during 20 years of observation, acting as the reference porphyria unit in Catalonia (from 6.0 to 7.5 million during this period). This would mean, as a tentative calculation (and with reference to an average population of 7 million inhabitants) an average incidence of 0.25 new cases/million inhabitants-year.The disease incidence was shown to be highly dependent on gender (33 women versus 2 males).The 35 patients had clinical symptoms which started as abdominal pain, nausea, vomiting and intestinal paresis, all accompanied by hyponatremia and other vegetative signs such as tachycardia and increased blood pressure, and emission of dark urine (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In 26 cases, clinical symptoms were reduced to autonomic type alterations. However, 9 patients also had altered PNS presented as ascending polyneuropathy with tetraparesis, along with anxiety, insomnia and psychomotor agitation. In 5 of these last cases, CNS involvement was also present in the form of seizures, confusional state and hallucinations. It is noteworthy that the 9 cases who developed this severe neurological condition experienced a delay of several months or even years in the diagnosis of porphyria,<a class="elsevierStyleCrossRef" href="#bib0135">11</a> being treated during that time with porphyrinogenic drugs such as dipyrone or hydantoins, which could have worsened the clinical features.Precipitating factors of the first acute porphyria crisis are reflected in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. It should be noted that crisis development is associated with a high incidence of stress and the fact that 60% of cases involve the coincidence of 2 or 3 causing factors.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>In all cases, treatment was started with hemin (Normosang®) at 3–4mg/kg doses by intravenous infusion for 3 days. This treatment allowed to stop the symptoms in all patients. However, sequelae persisted in cases of polyneuropathy. These improved progressively with the help of intensive rehabilitation, persisting, however, varying degrees of peripheral neuropathy and muscle deficiency.<a class="elsevierStyleCrossRef" href="#bib0140">12</a>Long-term monitoring has allowed classifying patients into 2 groups: A, patients with clinical symptoms who have had one or more attacks in a period of 2 years and then have remained asymptomatic or had only an isolated crisis clearly related with a trigger, and B, patients with recurrent clinical symptoms that required hemin administration periodically.The general characteristics of these patients are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Twenty-seven patients belonged to group A, 24 of them had one or more crises in a limited period of two years and subsequent remission, and 3 had one or more subsequent crises in this initial period, which were resolved with the administration of hemin. Eight patients were classified in group B for recurrent acute crises that required fortnightly or monthly administration of hemin for long periods of time.The 8 patients in group B presented abdominal pain, insomnia and agitation, repeatedly. Due to the risk of developing severe neurological clinical features, they were treated with hemin after symptom onset with rapid subjective improvement. Tachycardia or hyponatremia has not been found in most of these repeated crises, although early treatment initiation may have prevented their onset. In all cases, the onset of symptoms has been associated with stress and anxiety. In 5 of them, the clinical features have also been associated with calorie diets and other eating disorders.Six out of 8 patients with repeated crises (group B) had severe neurological involvement in the first crisis, while the neurological condition only developed in 3 out of 27 patients with sporadic crises (group A).Urinary excretion of heme precursors (PBG and ALA) has been found highly increased during acute crisis and remains elevated above normal values in all cases, but with marked differences. In most patients belonging to group A, PBG and ALA urinary concentration progressively declined over the years (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), although there were marked differences and irregularities in the speed of this decline. However, in all group B patients, urinary PBG and ALA excretions remain high over time (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), and the continued administration of hemin does not induce a gradual descent. Regarding drug administration in Group B patients, urinary PBG and ALA values clearly decreased after 24h of hemin administration, but these values increased again, reaching baseline values after 15 days of treatment (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>One of the patients in group B, in 2010, after 8 years of monthly treatment with hemin, accepted to finish this treatment, following clinical consensus and under strict medical monitoring. The abdominal pain was resolved by an orally administered glucose overload. There have been no new crises until the present time (2014). A progressive decrease in PBG and ALA elimination has been shown from the moment the administration of hemin was suspended (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). The remaining 7 patients in group B did not accept suspension of the regular hemin treatment due to fear associated with the emergence of a severe neurological crisis.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>94 relatives among 35 families were studied and 44 asymptomatic carriers were identified (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). All showed a decreased PBGD activity in red blood cells and the presence of that family's typical gene mutation. However, the PBG and ALA urinary excretion study has allowed to distinguish two groups: P1, with slightly elevated heme precursors in urine (PBG>1mmol/mol of creatinine, ALA>5), and P2, PBG and ALA in urine strictly normal. Most carriers (n=31, 70.5%) correspond to group P2, i.e., they do not present biochemical abnormalities, so that the study of these precursors in urine without a genetic or enzymatic analysis would fail to identify a carrier status.PBGD activity in red blood cells is decreased (approximately 50% from the normal value) in all patients and asymptomatic carriers, with no significant differences between the various groups (A, B, P1 and P2).Gene mutation was detected in all patients and carriers PBGD.<a class="elsevierStyleCrossRef" href="#bib0130">10</a> These mutations were classified into 2 groups: A, missense mutation, by amino acid change and, consequently, predictable residual activity of the mutant protein, and B, non-missense mutation, including deletions, stop-codon, splicing defects and, therefore, non-predictable residual activity (null mutation). Overall, patients showed (n=35), 21 cases of null mutations (60%) and 14 of missense mutations (40%) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).A high proportion of null mutations was found in group B patients (n=8) (6 patients, 75%) in comparison with missense (2 patients, 25%). However, group A showed (n=27) 15 null mutations (55%) compared to 12 missense (45%).Among relatives (n=44) there were 19 null mutation carriers (43%) versus 24 (54%) missense. The group of carriers with biochemical abnormalities (n=13) showed 7 null mutation carriers (54%) versus 6 (46%) missense. Finally, the group of carriers without biochemical abnormalities showed (n=31) 12 null mutations (39%) versus 19 missense mutations (61%).DiscussionThis series includes all AIP patients seen at Hospital Clínic of Barcelona, with Catalonia as its area of influence, with a population (2014) of 7.5 million. Most patients were not seen at first in the Hospital Clínic, as the start of the crisis is usually treated at the centre closest to the patient's home. However, once the period of initial severity had passed, patients were referred to the Hospital Clínic for definitive diagnosis and subsequent progression control. Mortality in this series was 0.As reference site, we have an approximate disease incidence indicator in our geographical area (0.25/million inhabitants-year, slightly higher than the calculated average in most European countries, which is 0.13/million inhabitants-year).<a class="elsevierStyleCrossRef" href="#bib0095">3</a>It is not possible to calculate the clinical penetrance of the disease without data on the general population's genetic defect prevalence. A study in France measured PBGD activity in 3305 blood donors, showing a prevalence of 0.06%.<a class="elsevierStyleCrossRef" href="#bib0145">13</a> However, no data are available in other European countries.The high number of latent cases observed in our family study indicates that AIP's clinical penetrance is low.<a class="elsevierStyleCrossRef" href="#bib0090">2</a> Our results show a large number of carriers in which the enzymatic and genetic deficiency do not incur in the development of the disease, neither have an impact on biochemical alterations. This shows that, in most carriers, liver homeostasis offsets PBGD deficiency without necessarily resulting in overproduction of heme precursors. Only the concurrence of major precipitating factors may, therefore, lead to a metabolic pathway decompensation. It is noteworthy that this decompensation with PBG and ALA accumulation may occur in other types of porphyria (for example in the variegate porphyria), where there is no PBGD gene mutation and yet, it has never been described in non-carriers of porphyria.<a class="elsevierStyleCrossRef" href="#bib0115">7</a>Our series confirms that the autosomal dominant transmission disease is mainly developed in women (94.3%). This high proportion of females confirms observations made in other countries.<a class="elsevierStyleCrossRef" href="#bib0100">4</a> It also confirms that the disease never develops before puberty, and that there is a critical age band (60% of the cases in our series were <30 years of age).The possible explanation for women's greater susceptibility to AIP has not been fully figured out. The human liver is sexually dimorphic with respect to the expression of numerous genes, including ALAS1. A complex network of transcription factors controls gene expression in the liver, and numerous transcription factors are under the influence of the main hormonal axes, which would explain sex susceptibility differences to ALAS1<a class="elsevierStyleCrossRef" href="#bib0115">7</a> induction.In addition to hormonal factors, our series highlights the role of stress, surgical procedures with administration of drugs, diets, infections or self-medication as precipitating factors.Delayed diagnosis is shown as a clear risk factor associated with PNS involvement, which points to the need of being alert and requesting urgent porphyrins tests at the onset, especially childbearing age women presenting unexplained abdominal pain, hyponatremia or dark urine.Fasting has shown to induce the ALAS1 gene in the liver through the transcriptional coactivator PGCα.<a class="elsevierStyleCrossRef" href="#bib0150">14</a> The same mechanism would explain the beneficial effect of glucose treatment in acute attack, and also the beneficial effect of a high-calorie diet as a protective factor. Similarly, various forms of stress, such as traumatic, mental or psychological can induce the ALAS1 gene through stimulation of the adrenal-hypothalamic-pituitary axis.<a class="elsevierStyleCrossRef" href="#bib0115">7</a>Our series clearly illustrates how a majority of patients with AIP can achieve lasting clinical remission. Lifestyle, with minimization of stress, body weight and a proper diet, appears to be a major factor in determining disease remission course.However, PBG and ALA urinary excretion after an acute attack is not normalized as in other types of acute porphyria (e.g. variegate porphyria), rather, it remains high for long periods of time.<a class="elsevierStyleCrossRef" href="#bib0155">15</a> The mechanisms involved in this non biochemical remission are unknown and are one of the possible factors contributing to the clinical recurrence. The sustained ALAS1 gene overactivity could be the cause of hepatic overproduction of PBG/ALA.Still, long-term monitoring allows to observe a gradual decline in urinary concentrations of heme precursors in a significant number of patients during clinical remission. The slope of this reduction is highly variable in our patients, although in some cases it has been faster than that described by other authors, who have calculated a PBG urinary half-life of 10.6 years.<a class="elsevierStyleCrossRef" href="#bib0155">15</a>Recurrent patients constitute a major problem in the field of acute porphyria. Periodic administration of hemin (for example, every 2–3 weeks) during long periods results in avoiding severe crises, yet, it does not induce a clinical or biochemical remission. In our series we have not been able to see a gradual decrease in the urinary concentrations of PBG/ALA in this type of patients. Recurrent features can be sustained in the liver by the transient effect of hemin on the ALAS1 gene and the concomitant induction of heme oxygenase, increasing heme degradation and quickly losing the negative feedback effect. This hypothesis is perfectly adjusted to the rebound effect of PBG/ALA in urine, observed in our patients (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). The long-term unsustainability of this treatment, venous access problems, or possible accumulation of iron in the liver have led in some cases to liver transplantation<a class="elsevierStyleCrossRef" href="#bib0120">8</a> or the design of gene therapy strategies, presently under evaluation.<a class="elsevierStyleCrossRef" href="#bib0160">16</a>Although PBGD activity in peripheral blood is lower in recurrent cases, these patients may present a more pronounced liver enzyme deficiency. This could be explained by null type mutations in the PBGD gene, which imply a lack of mutant protein compared to missense mutations, which can allow a degree of residual activity. Our data do not confirm this hypothesis, because although null mutations are more common in recurrent group patients (6 of 8), 2 patients with missense (R173W) mutation had recurrent attacks. The data, however, would support the hypothesis of a lower risk of recurrence in missense mutation cases.It is noteworthy that a patient in our series (male with mutation R173W)<a class="elsevierStyleCrossRef" href="#bib0130">10</a> could interrupt a prolonged treatment with hemin without recurrence of acute clinical symptoms or increased PBG/ALA in urine. Thus the possibility of leaving hepatic dysregulation in a natural way is shown by the administration of hemin/induction of heme oxygenase/ALAS1 induction/new hemin administration.Thus, factors associated with lifestyle, right nutrition, minimizing stress, may not only be important in preventing acute attacks of AIP, but also facilitate remission in cases of recurrence.Conflict of interestsThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres625676" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec638836" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres625677" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec638837" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and method" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of interests" ] 9 => array:2 [ "identificador" => "xack210878" "titulo" => "Acknowledgements" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-05-12" "fechaAceptado" => "2014-06-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec638836" "palabras" => array:4 [ 0 => "Acute intermittent porphyria" 1 => "Hemin" 2 => "Porphobilinogen deaminase" 3 => "Neurovisceral crisis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec638837" "palabras" => array:4 [ 0 => "Porfiria aguda intermitente" 1 => "Hemina" 2 => "Porfobilinógeno deaminasa" 3 => "Crisis neurovisceral" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and objectivesAcute intermittent porphyria (AIP) is a rare disease that results from a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. AIP carriers are at risk of presenting acute neurovisceral attacks associated with overproduction of heme-precursors in the liver. Patients and methodWe report the characteristics of all AIP patients attended in the Hospital Clinic of Barcelona during the years 1993–2013 and their long-term follow-up. ResultsThirty-five AIP patients (33 women, 2 men) experienced acute attacks. Treatment with hemin resolved the acute neurovisceral crisis in all cases. Nine patients presented peripheral neuropathy and persistent sequelae. Long-term follow-up allowed classifying the patients into groups: A, patients with acute symptoms during 1–2 years and subsequent long-lasting clinical remission (n=24) or a few sporadic crises (n=3), and B, patients with recurrent attacks requiring chronic administration of hemin (n=8). In a majority of the patients of group A, the urinary excretion of heme-precursors decreased gradually over time. However, the chronic hemin regime did not induce a decline of urinary heme-precursors in the patients of group B. Additionally, we identified 44 asymptomatic AIP carriers, most (70.5%) with normal values of heme-precursors in urine. ConclusionsA majority of the AIP patients of our series achieved a long-lasting clinical remission. A minority (23%) presented recurrent attacks that required chronic hemin infusions without feasible interruption and without long-term biochemical remission. The type of mutation within the porphobilinogen deaminase gene and also life-style related factors may determine remission time-course." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Fundamento y objetivosLa porfiria aguda intermitente (PAI) es una enfermedad causada por un defecto en la enzima porfobilinógeno deaminasa que cataliza la tercera etapa de síntesis del hemo. Los portadores pueden presentar ataques neuroviscerales agudos tras sobreproducción hepática de precursores del hemo. Pacientes y métodoSe presentan las características de todos los pacientes con PAI atendidos en el Hospital Clínic de Barcelona entre los años 1993-2013, y su seguimiento a largo plazo. ResultadosTreinta y cinco pacientes con PAI (33 mujeres y 2 varones) presentaron ataques agudos neuroviscerales. El tratamiento con hemina resolvió el cuadro agudo en todos los casos. Nueve pacientes presentaron polineuropatía y secuelas persistentes. El seguimiento permitió clasificar a los pacientes en: A, con sintomatología aguda durante 1-2 años y posterior remisión duradera (n=24) o bien alguna crisis puntual (n=3), y B, con ataques recurrentes que requirieron administración crónica de hemina (n=8). En la mayoría de los pacientes del grupo A la concentración urinaria de precursores del hemo fue disminuyendo progresivamente, mientras que en el grupo B esta se mantuvo elevada sin descenso observable a largo término. Adicionalmente, el estudio familiar permitió identificar 44 portadores asintomáticos, la mayoría (70,5%) con valores normales de precusores del hemo en orina. ConclusionesUna mayoría de pacientes con PAI de nuestra serie logró una remisión clínica duradera. Una minoría presenta ataques recurrentes, sin que el tratamiento crónico con hemina haga factible su interrupción ni induzca remisión bioquímica a largo plazo. El tipo de mutación en el gen de la porfobilinógeno deaminasa, y también factores asociados al estilo de vida, pueden determinar el curso de la remisión." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Herrero C, Badenas C, Aguilera P, To-Figueras J. Porfiria aguda intermitente: seguimiento a largo término de 35 pacientes. Med Clin (Barc). 2015;145:332–337." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1275 "Ancho" => 1624 "Tamanyo" => 101094 ] ] "descripcion" => array:1 [ "en" => "Long-term progression of urinary concentration of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) in one patient in group A. Concentration of PBG and ALA expressed in mmol/mol creatinine." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1205 "Ancho" => 1635 "Tamanyo" => 206108 ] ] "descripcion" => array:1 [ "en" => "Long-term progression of urinary concentration of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) in one patient in group B, under maintenance treatment with hemin. PBG and ALA concentration expressed in mmol/mol creatinine." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1072 "Ancho" => 1559 "Tamanyo" => 139937 ] ] "descripcion" => array:1 [ "en" => "Short term oscillation of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) concentration in a group B patient after administration of hemin. PBG and ALA concentration expressed in mmol/mol creatinine." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1389 "Ancho" => 1577 "Tamanyo" => 133653 ] ] "descripcion" => array:1 [ "en" => "Long-term progression of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) concentration in one group B patient, during the period of treatment with hemin (1–8 years) and after stopping the treatment (8–10 years). PBG and ALA concentration expressed in mmol/mol creatinine." ] ] 4 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "A: sporadic crises; B: recurrent crises; PBGD: porphobilinogen deaminase enzyme; P1: with a PBG and ALA increase in urine; P2: normal porphobilinogen and delta-aminolevulinic acid in urine; CNS: central nervous system; PNS: peripheral nervous system; ANS: autonomic nervous system." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Patients</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Carriers</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">A \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">B \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P1 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P2 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27 (77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 (23) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 (29.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31 (70.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Average age (ends) at the time of the study, years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">41.35 (22–76) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42.7 (22–76) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 (22–58) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43.4 (23–84) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43 (28–61) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39.8 (23–84) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 (94.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age at first crisis (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28.2 (17–46) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26.4 (17–39) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29.8 (21–46) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">15–20 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (11.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">20–30 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 (51.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">30–40 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (34.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">40–50 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (2.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Isolated ANS involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 (74.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANS, PNS and CNS involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (25.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PBGD activity in red blood cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">63% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">66% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">61.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">67 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mutations PBGD missense/null \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14/21 (0.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12/15 (0.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/6 (0.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24/19 (1.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6/7 (0.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.19 (1.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Follow up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–39 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–39 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–13 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–31 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–31 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–14 years \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1026502.png" ] ] ] ] "descripcion" => array:1 [ "en" => "General characteristics of the group of patients and relatives studied." ] ] 5 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Data expressed as n (%)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stress and/or psychiatric disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (40) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Surgery under anaesthesia<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 (31.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (28) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Calorie diet \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (25) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (20) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Menstruation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (14) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">More than one factor<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 (57.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1026501.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Surgery, childbirth, abortion." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Two factors in 10 cases; 3 factors in 10 cases." ] ] ] "descripcion" => array:1 [ "en" => "First crisis triggers." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Porphyrias" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H. Puy" 1 => "L. Gouya" 2 => "J.C. Deybach" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(09)61925-5" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2010" "volumen" => "375" "paginaInicial" => "924" "paginaFinal" => "937" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20226990" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0090" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute intermittent porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B. Grandchamp" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2007-1007136" "Revista" => array:6 [ "tituloSerie" => "Semin Liver Dis" "fecha" => "1998" "volumen" => "18" "paginaInicial" => "17" "paginaFinal" => "24" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9516674" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0095" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The incidence of inherited porphyrias in Europe" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "G. Elder" 1 => "P. Harper" 2 => "M. Badminton" 3 => "S. Sandberg" 4 => "J.C. Deybach" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10545-012-9544-4" "Revista" => array:6 [ "tituloSerie" => "J Inherit Metab Dis" "fecha" => "2013" "volumen" => "36" "paginaInicial" => "849" "paginaFinal" => "857" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23114748" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0100" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R. Kauppinen" 1 => "P. Mustajoki" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Medicine (Baltimore)" "fecha" => "1992" "volumen" => "71" "paginaInicial" => "1" "paginaFinal" => "13" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0105" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An analysis of 112 acute porphyric attacks in Cape Town South Africa: evidence that acute intermittent porphyria and variegate porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.J. Hift" 1 => "P.N. Meissner" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Medicine (Baltimore)" "fecha" => "2005" "volumen" => "84" "paginaInicial" => "48" "paginaFinal" => "60" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0110" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute porphyrias: pathogenesis of neurological manifestations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "U.A. Meyer" 1 => "M.M. Schuurmans" 2 => "R.L. Lindberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2007-1007139" "Revista" => array:6 [ "tituloSerie" => "Semin Liver Dis" "fecha" => "1998" "volumen" => "18" "paginaInicial" => "43" "paginaFinal" => "52" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9516677" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0115" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Outside the box: genomic approach to acute porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S. Thunell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Physiol Res" "fecha" => "2006" "volumen" => "55" "paginaInicial" => "43" "paginaFinal" => "66" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0120" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver transplantation as a cure for acute intermittent porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Z.F. Soonawalla" 1 => "T. Orug" 2 => "M.N. Badminton" 3 => "G.H. Elder" 4 => "J.M. Rhodes" 5 => "S.R. Bramhall" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(04)15646-8" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2004" "volumen" => "363" "paginaInicial" => "705" "paginaFinal" => "706" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15001330" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0125" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "European specialist porphyria laboratories: diagnostic strategies, analytical quality, clinical interpretation, and reporting as assessed by an external quality assurance program" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.K. Aarsand" 1 => "J.H. Villanger" 2 => "E. Støle" 3 => "J.C. Deybach" 4 => "J. Marsden" 5 => "J. To-Figueras" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1373/clinchem.2011.170357" "Revista" => array:6 [ "tituloSerie" => "Clin Chem" "fecha" => "2011" "volumen" => "57" "paginaInicial" => "1514" "paginaFinal" => "1523" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21937752" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0130" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic and biochemical characterization of 16 acute intermittent porphyria cases with a high prevalence of the R173W mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. To-Figueras" 1 => "C. Badenas" 2 => "C. Carrera" 3 => "C. Muñoz" 4 => "M. Mila" 5 => "M. Lecha" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10545-006-0344-6" "Revista" => array:6 [ "tituloSerie" => "J Inherit Metab Dis" "fecha" => "2006" "volumen" => "29" "paginaInicial" => "580" "paginaFinal" => "585" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16817012" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0135" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Late diagnosis of a case of acute intermittent porphyria in the ICU" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A.J. Betbesé" 1 => "L. Zapata" 2 => "C. Martínez-Brú" 3 => "C. Herrero" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.medin.2009.09.009" "Revista" => array:5 [ "tituloSerie" => "Med Intensiva" "fecha" => "2010" "volumen" => "34" "paginaInicial" => "358" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19939505" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0140" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prognosis of polyneuropathy associated to intermittent acute porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Vallès" 1 => "J. Benito" 2 => "R. Pelayo" 3 => "J. Vidal" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Med Clin (Barc)" "fecha" => "2011" "volumen" => "137" "paginaInicial" => "191" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0145" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Nordmann" 1 => "H. Puy" 2 => "V. da Silva" 3 => "S. Simonin" 4 => "A.M. Robreau" 5 => "C. Bonaiti" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Intern Med" "fecha" => "1997" "volumen" => "242" "paginaInicial" => "213" "paginaFinal" => "217" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9350165" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0150" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Handschin" 1 => "J. Lin" 2 => "J. Rhee" 3 => "A.K. Peyer" 4 => "S. Chin" 5 => "P.H. Wu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cell.2005.06.040" "Revista" => array:6 [ "tituloSerie" => "Cell" "fecha" => "2005" "volumen" => "122" "paginaInicial" => "505" "paginaFinal" => "515" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16122419" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0155" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Urinary excretion of porphyrins, porphobilinogen and δ-aminolaevulinic acid following an attack of acute intermittent porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.T. Marsden" 1 => "D. Rees" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jclinpath-2012-201367" "Revista" => array:6 [ "tituloSerie" => "J Clin Pathol" "fecha" => "2014" "volumen" => "67" "paginaInicial" => "60" "paginaFinal" => "65" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23908454" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0160" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute intermittent porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Pañeda" 1 => "E. Lopez-Franco" 2 => "C. Kaeppel" 3 => "C. Unzu" 4 => "A.G. Gil-Royo" 5 => "D. D’Avola" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/hum.2013.166" "Revista" => array:6 [ "tituloSerie" => "Hum Gene Ther" "fecha" => "2013" "volumen" => "24" "paginaInicial" => "1007" "paginaFinal" => "1017" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24070415" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack210878" "titulo" => "Acknowledgements" "texto" => "The authors want to thank the Porphyria's Unit's nursing staff at the Hospital Clínic of Barcelona for the many years of continued support." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000014500000008/v1_201604030058/S238702061600108X/v1_201604030058/en/main.assets" "Apartado" => array:4 [ "identificador" => "43310" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000014500000008/v1_201604030058/S238702061600108X/v1_201604030058/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702061600108X?idApp=UINPBA00004N"]

Statistics

Original article

Acute intermittent porphyria: Long-term follow up of 35 patients

Porfiria aguda intermitente: seguimiento a largo término de 35 pacientes

Carmen Herreroa,b, Celia Badenasa,c, Paula Aguileraa,b, Jordi To-Figuerasa,c,

Corresponding author

JTO@clinic.ub.es

Corresponding author.

a Unidad de Porfirias, Grupo de Enfermedades Minoritarias del Adulto, Hospital Clinic, Barcelona, Spain

b Servei de Dermatologia, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain

c Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain

Read

Times
was read the article

Total PDF

Total HTML

Share statistics

 array:24 [
  "pii" => "S238702061600108X"
  "issn" => "23870206"
  "doi" => "10.1016/j.medcle.2016.02.043"
  "estado" => "S300"
  "fechaPublicacion" => "2015-10-21"
  "aid" => "3076"
  "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;. All rights reserved"
  "copyrightAnyo" => "2014"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "fla"
  "cita" => "Med Clin. 2015;145:332-7"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:2 [
    "total" => 2
    "HTML" => 2
  ]
  "Traduccion" => array:1 [
    "es" => array:19 [
      "pii" => "S0025775314005739"
      "issn" => "00257753"
      "doi" => "10.1016/j.medcli.2014.06.012"
      "estado" => "S300"
      "fechaPublicacion" => "2015-10-21"
      "aid" => "3076"
      "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
      "documento" => "article"
      "crossmark" => 1
      "subdocumento" => "fla"
      "cita" => "Med Clin. 2015;145:332-7"
      "abierto" => array:3 [
        "ES" => false
        "ES2" => false
        "LATM" => false
      ]
      "gratuito" => false
      "lecturas" => array:2 [
        "total" => 47
        "formatos" => array:2 [
          "HTML" => 28
          "PDF" => 19
        ]
      ]
      "es" => array:13 [
        "idiomaDefecto" => true
        "cabecera" => "<span class="elsevierStyleTextfn">Original</span>"
        "titulo" => "Porfiria aguda intermitente&#58; seguimiento a largo t&#233;rmino de 35 pacientes"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "tieneResumen" => array:2 [
          0 => "es"
          1 => "en"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "332"
            "paginaFinal" => "337"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Acute intermittent porphyria&#58; Long-term follow up of 35 patients"
          ]
        ]
        "contieneResumen" => array:2 [
          "es" => true
          "en" => true
        ]
        "contieneTextoCompleto" => array:1 [
          "es" => true
        ]
        "contienePdf" => array:1 [
          "es" => true
        ]
        "resumenGrafico" => array:2 [
          "original" => 0
          "multimedia" => array:7 [
            "identificador" => "fig0020"
            "etiqueta" => "Figura 4"
            "tipo" => "MULTIMEDIAFIGURA"
            "mostrarFloat" => true
            "mostrarDisplay" => false
            "figura" => array:1 [
              0 => array:4 [
                "imagen" => "gr4.jpeg"
                "Alto" => 1424
                "Ancho" => 1576
                "Tamanyo" => 133211
              ]
            ]
            "descripcion" => array:1 [
              "es" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Evoluci&#243;n a largo t&#233;rmino de la concentraci&#243;n de porfobilin&#243;geno &#40;PBG&#41; y &#225;cido delta-aminolevul&#237;nico &#40;ALA&#41; en un paciente del grupo B&#44; durante el per&#237;odo de tratamiento con hemina &#40;1-8 a&#241;os&#41; y despu&#233;s de suspender este tratamiento &#40;8-10 a&#241;os&#41;&#46; Concentraci&#243;n de PBG y ALA expresada en mmol&#47;mol de creatinina&#46;</p>"
            ]
          ]
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "Carmen Herrero, Celia Badenas, Paula Aguilera, Jordi To-Figueras"
            "autores" => array:4 [
              0 => array:2 [
                "nombre" => "Carmen"
                "apellidos" => "Herrero"
              ]
              1 => array:2 [
                "nombre" => "Celia"
                "apellidos" => "Badenas"
              ]
              2 => array:2 [
                "nombre" => "Paula"
                "apellidos" => "Aguilera"
              ]
              3 => array:2 [
                "nombre" => "Jordi"
                "apellidos" => "To-Figueras"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "S238702061600108X"
          "doi" => "10.1016/j.medcle.2016.02.043"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => false
            "ES2" => false
            "LATM" => false
          ]
          "gratuito" => false
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702061600108X?idApp=UINPBA00004N"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775314005739?idApp=UINPBA00004N"
      "url" => "/00257753/0000014500000008/v1_201509220049/S0025775314005739/v1_201509220049/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S2387020616001182"
    "issn" => "23870206"
    "doi" => "10.1016/j.medcle.2016.02.053"
    "estado" => "S300"
    "fechaPublicacion" => "2015-10-21"
    "aid" => "3233"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
    "documento" => "simple-article"
    "crossmark" => 1
    "subdocumento" => "crp"
    "cita" => "Med Clin. 2015;145:338-40"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 2
      "HTML" => 2
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Brief report</span>"
      "titulo" => "Occupational semicircular lipoatrophy associated with serum adipokine abnormalities"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "338"
          "paginaFinal" => "340"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Lipoatrofia semicircular de etiolog&#237;a laboral asociada a alteraciones s&#233;ricas de adipocinas"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Luis Reinoso-Barbero, Ram&#243;n D&#237;az-Garrido, Mar&#237;a-Fernanda Gonz&#225;lez-G&#243;mez, Jos&#233; Olarrea, F&#233;lix G&#243;mez-Gallego, Fernando Bandr&#233;s"
          "autores" => array:6 [
            0 => array:2 [
              "nombre" => "Luis"
              "apellidos" => "Reinoso-Barbero"
            ]
            1 => array:2 [
              "nombre" => "Ram&#243;n"
              "apellidos" => "D&#237;az-Garrido"
            ]
            2 => array:2 [
              "nombre" => "Mar&#237;a-Fernanda"
              "apellidos" => "Gonz&#225;lez-G&#243;mez"
            ]
            3 => array:2 [
              "nombre" => "Jos&#233;"
              "apellidos" => "Olarrea"
            ]
            4 => array:2 [
              "nombre" => "F&#233;lix"
              "apellidos" => "G&#243;mez-Gallego"
            ]
            5 => array:2 [
              "nombre" => "Fernando"
              "apellidos" => "Bandr&#233;s"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S002577531500072X"
        "doi" => "10.1016/j.medcli.2014.12.024"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => false
          "ES2" => false
          "LATM" => false
        ]
        "gratuito" => false
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577531500072X?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616001182?idApp=UINPBA00004N"
    "url" => "/23870206/0000014500000008/v1_201604030058/S2387020616001182/v1_201604030058/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S2387020616001108"
    "issn" => "23870206"
    "doi" => "10.1016/j.medcle.2016.02.045"
    "estado" => "S300"
    "fechaPublicacion" => "2015-10-21"
    "aid" => "3122"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Med Clin. 2015;145:327-31"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 4
      "HTML" => 4
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
      "titulo" => "Amyloidosis complicating spondyloarthropathies&#58; Study of 15 cases"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "327"
          "paginaFinal" => "331"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Amiloidosis secundaria a espondiloartritis&#58; estudio de 15 casos"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Samantha Rodr&#237;guez-Muguruza, Melania Mart&#237;nez-Morillo, Susana Holgado, Xavier Saenz-Sarda, Lourdes Mateo, Xavier Tena, Alejandro Oliv&#233;"
          "autores" => array:7 [
            0 => array:2 [
              "nombre" => "Samantha"
              "apellidos" => "Rodr&#237;guez-Muguruza"
            ]
            1 => array:2 [
              "nombre" => "Melania"
              "apellidos" => "Mart&#237;nez-Morillo"
            ]
            2 => array:2 [
              "nombre" => "Susana"
              "apellidos" => "Holgado"
            ]
            3 => array:2 [
              "nombre" => "Xavier"
              "apellidos" => "Saenz-Sarda"
            ]
            4 => array:2 [
              "nombre" => "Lourdes"
              "apellidos" => "Mateo"
            ]
            5 => array:2 [
              "nombre" => "Xavier"
              "apellidos" => "Tena"
            ]
            6 => array:2 [
              "nombre" => "Alejandro"
              "apellidos" => "Oliv&#233;"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0025775314006964"
        "doi" => "10.1016/j.medcli.2014.06.019"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => false
          "ES2" => false
          "LATM" => false
        ]
        "gratuito" => false
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775314006964?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616001108?idApp=UINPBA00004N"
    "url" => "/23870206/0000014500000008/v1_201604030058/S2387020616001108/v1_201604030058/en/main.assets"
  ]
  "en" => array:21 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Acute intermittent porphyria&#58; Long-term follow up of 35 patients"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "332"
        "paginaFinal" => "337"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Carmen Herrero, Celia Badenas, Paula Aguilera, Jordi To-Figueras"
        "autores" => array:4 [
          0 => array:3 [
            "nombre" => "Carmen"
            "apellidos" => "Herrero"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Celia"
            "apellidos" => "Badenas"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Paula"
            "apellidos" => "Aguilera"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          3 => array:4 [
            "nombre" => "Jordi"
            "apellidos" => "To-Figueras"
            "email" => array:1 [
              0 => "JTO&#64;clinic&#46;ub&#46;es"
            ]
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:3 [
          0 => array:3 [
            "entidad" => "Unidad de Porfirias&#44; Grupo de Enfermedades Minoritarias del Adulto&#44; Hospital Clinic&#44; Barcelona&#44; Spain"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Servei de Dermatologia&#44; Hospital Cl&#237;nic&#44; Institut d&#8217;Investigacions Biom&#232;diques August Pi i Sunyer &#40;IDIBAPS&#41;&#44; Universitat de Barcelona&#44; Barcelona&#44; Spain"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Servei de Bioqu&#237;mica i Gen&#232;tica Molecular&#44; Hospital Cl&#237;nic&#44; Institut d&#8217;Investigacions Biom&#232;diques August Pi i Sunyer &#40;IDIBAPS&#41;&#44; Universitat de Barcelona&#44; Barcelona&#44; Spain"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Porfiria aguda intermitente&#58; seguimiento a largo t&#233;rmino de 35 pacientes"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1205
            "Ancho" => 1635
            "Tamanyo" => 206108
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Long-term progression of urinary concentration of porphobilinogen &#40;PBG&#41; and delta-aminolevulinic acid &#40;ALA&#41; in one patient in group B&#44; under maintenance treatment with hemin&#46; PBG and ALA concentration expressed in mmol&#47;mol creatinine&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Acute intermittent porphyria &#40;AIP&#41; is a disease caused by a defect in the enzyme porphobilinogen deaminase &#40;PBGD&#59; also called hydroxymethylbilane synthetase&#44; EC 2&#46;5&#46;1&#46;61&#41;&#44; which catalyses the third step of heme synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a> The enzyme deficiency results from the existence of mutations in the <span class="elsevierStyleItalic">PBGD</span> gene located at chromosomal region 11q24&#46;1 and consisting of 15 exons&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> The disease is transmitted in an autosomal dominant way with a low clinical penetrance&#44; although&#44; so far&#44; this has not been accurately estimated&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The annual incidence of new cases in most European countries has been estimated at 0&#46;13 per million inhabitants&#44; except in Sweden&#44; which has a higher incidence due to founder effects and genetic migration&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">3</span></a> Subjects who carry the genetic defect have potential risk of very severe acute neurovisceral attacks&#46; This is much more common in women than in men&#44; and never happens before puberty&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In its active mode&#44; AIP is in the form of an acute dysfunction of the central nervous system &#40;CNS&#41;&#44; autonomic and peripheral &#40;PNS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a> Patients come to the emergency room with acute abdominal pain&#44; tachycardia&#44; hypertension&#44; seizures&#44; psychiatric disorders&#44; and hyponatremia&#46; PNS involvement can induce motor neuropathy&#44; which can cause tetraparesia and even respiratory paralysis&#46; The clinical features are associated with a sharp hepatic overproduction of heme precursors&#44; porphobilinogen &#40;PBG&#41; and delta-aminolevulinic acid &#40;ALA&#41; after induction of the ALA synthetase 1 <span class="elsevierStyleItalic">&#40;ALAS1&#41; gene</span>&#46; According to the most plausible pathophysiological explanation&#44; ALA hepatic export and the resulting cellular toxicity could be the cause of neurological crises&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The acute attacks result from the concomitance of the genetic&#47;enzymatic underlying defect and hormonal or other precipitating factors &#40;hypocaloric diet&#44; stress&#44; drug administration&#44; infections&#44; etc&#46;&#41; that can induce expression of the <span class="elsevierStyleItalic">ALAS1</span> gene in the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a> The abrupt induction of the first part of the metabolic pathway&#44; coupled with liver PBGD underactivity&#44; results in PBG and ALA accumulation&#46; The <span class="elsevierStyleItalic">ALAS1</span> gene is partly controlled by a heme negative <span class="elsevierStyleItalic">feedback</span> mechanism&#44; last product of the metabolic pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> In case of acute attack&#44; the intravenous administration of hemin &#40;human hemin stabilized with arginine&#44; Normosang<span class="elsevierStyleSup">&#174;</span>&#41;&#44; which restores the hepatic heme reserve and reduces <span class="elsevierStyleItalic">ALAS1</span> induction is a measure of high therapeutic effectiveness that&#44; in most cases&#44; resolves neurovisceral crises&#44; although not allowing a complete biochemical remission&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> The administration of glucose also has an inhibitor <span class="elsevierStyleItalic">ALAS1</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> effect &#40;though less effective&#41;&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">A minority of patients with AIP experience recurrent attacks requiring repeated heme administration for long periods of time&#46; Liver transplantation has taken place in some very severe recurrent cases&#46; In these cases&#44; the transplant has cured the disease&#44; thus demonstrating its hepatic origin&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Our study is the summary of the experience &#40;expanded over several decades&#41; in the diagnosis&#44; treatment and research of the AIP in the Porphyria&#39;s Unit &#40;Department of Dermatology and Biomedical Diagnostic Centre&#41; of the Hospital Cl&#237;nic of Barcelona&#46; All the cases treated in this unit between 1993 and 2013 are presented herein&#44; together with a description of their clinical and biochemical characteristics&#46; The prevalence of the disease in our country has been estimated&#44; as well as a list of precipitating factors and a progression categorization of recurrent cases&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and method</span><p id="par0035" class="elsevierStylePara elsevierViewall">Demographic&#44; clinical&#44; biochemical and family data of all patients with AIP who were treated consecutively by the Porphyria&#39;s Unit of the Hospital Cl&#237;nic of Barcelona between the years 1993 and 2013 were collected&#46; During this period&#44; 35 patients were treated and 94 relatives were studied&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">AIP diagnosis in patients was made according to the criteria agreed by the <span class="elsevierStyleItalic">European Porphyria Initiative</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">9</span></a> These criteria include&#58; characteristic clinical symptoms&#44; significant PBG&#44; ALA and urine porphyrins increase&#44; fluorescence emission peak in plasma&#44; porphyrins and isomers high-performance liquid chromatography in stool&#44; decreased PBGD enzyme activity in red blood cells and&#44; finally&#44; confirmation by PBGD gene mutation detection&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The classification criteria in clinically asymptomatic relatives had to do with the presence of <span class="elsevierStyleItalic">PBGD</span> gene mutation and a low activity in the PBGD enzyme in blood&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">35 new patients were identified with AIP during 20 years of observation&#44; acting as the reference porphyria unit in Catalonia &#40;from 6&#46;0 to 7&#46;5 million during this period&#41;&#46; This would mean&#44; as a tentative calculation &#40;and with reference to an average population of 7 million inhabitants&#41; an average incidence of 0&#46;25 new cases&#47;million inhabitants-year&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The disease incidence was shown to be highly dependent on gender &#40;33 women versus 2 males&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The 35 patients had clinical symptoms which started as abdominal pain&#44; nausea&#44; vomiting and intestinal paresis&#44; all accompanied by hyponatremia and other vegetative signs such as tachycardia and increased blood pressure&#44; and emission of dark urine &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">In 26 cases&#44; clinical symptoms were reduced to autonomic type alterations&#46; However&#44; 9 patients also had altered PNS presented as ascending polyneuropathy with tetraparesis&#44; along with anxiety&#44; insomnia and psychomotor agitation&#46; In 5 of these last cases&#44; CNS involvement was also present in the form of seizures&#44; confusional state and hallucinations&#46; It is noteworthy that the 9 cases who developed this severe neurological condition experienced a delay of several months or even years in the diagnosis of porphyria&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> being treated during that time with porphyrinogenic drugs such as dipyrone or hydantoins&#44; which could have worsened the clinical features&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Precipitating factors of the first acute porphyria crisis are reflected in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; It should be noted that crisis development is associated with a high incidence of stress and the fact that 60&#37; of cases involve the coincidence of 2 or 3 causing factors&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In all cases&#44; treatment was started with hemin &#40;Normosang<span class="elsevierStyleSup">&#174;</span>&#41; at 3&#8211;4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg doses by intravenous infusion for 3 days&#46; This treatment allowed to stop the symptoms in all patients&#46; However&#44; sequelae persisted in cases of polyneuropathy&#46; These improved progressively with the help of intensive rehabilitation&#44; persisting&#44; however&#44; varying degrees of peripheral neuropathy and muscle deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Long-term monitoring has allowed classifying patients into 2 groups&#58; A&#44; patients with clinical symptoms who have had one or more attacks in a period of 2 years and then have remained asymptomatic or had only an isolated crisis clearly related with a trigger&#44; and B&#44; patients with recurrent clinical symptoms that required hemin administration periodically&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The general characteristics of these patients are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Twenty-seven patients belonged to group A&#44; 24 of them had one or more crises in a limited period of two years and subsequent remission&#44; and 3 had one or more subsequent crises in this initial period&#44; which were resolved with the administration of hemin&#46; Eight patients were classified in group B for recurrent acute crises that required fortnightly or monthly administration of hemin for long periods of time&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The 8 patients in group B presented abdominal pain&#44; insomnia and agitation&#44; repeatedly&#46; Due to the risk of developing severe neurological clinical features&#44; they were treated with hemin after symptom onset with rapid subjective improvement&#46; Tachycardia or hyponatremia has not been found in most of these repeated crises&#44; although early treatment initiation may have prevented their onset&#46; In all cases&#44; the onset of symptoms has been associated with stress and anxiety&#46; In 5 of them&#44; the clinical features have also been associated with calorie diets and other eating disorders&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Six out of 8 patients with repeated crises &#40;group B&#41; had severe neurological involvement in the first crisis&#44; while the neurological condition only developed in 3 out of 27 patients with sporadic crises &#40;group A&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Urinary excretion of heme precursors &#40;PBG and ALA&#41; has been found highly increased during acute crisis and remains elevated above normal values in all cases&#44; but with marked differences&#46; In most patients belonging to group A&#44; PBG and ALA urinary concentration progressively declined over the years &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; although there were marked differences and irregularities in the speed of this decline&#46; However&#44; in all group B patients&#44; urinary PBG and ALA excretions remain high over time &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; and the continued administration of hemin does not induce a gradual descent&#46; Regarding drug administration in Group B patients&#44; urinary PBG and ALA values clearly decreased after 24<span class="elsevierStyleHsp" style=""></span>h of hemin administration&#44; but these values increased again&#44; reaching baseline values after 15 days of treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">One of the patients in group B&#44; in 2010&#44; after 8 years of monthly treatment with hemin&#44; accepted to finish this treatment&#44; following clinical consensus and under strict medical monitoring&#46; The abdominal pain was resolved by an orally administered glucose overload&#46; There have been no new crises until the present time &#40;2014&#41;&#46; A progressive decrease in PBG and ALA elimination has been shown from the moment the administration of hemin was suspended &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The remaining 7 patients in group B did not accept suspension of the regular hemin treatment due to fear associated with the emergence of a severe neurological crisis&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">94 relatives among 35 families were studied and 44 asymptomatic carriers were identified &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; All showed a decreased PBGD activity in red blood cells and the presence of that family&#39;s typical gene mutation&#46; However&#44; the PBG and ALA urinary excretion study has allowed to distinguish two groups&#58; P1&#44; with slightly elevated heme precursors in urine &#40;PBG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>mmol&#47;mol of creatinine&#44; ALA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>5&#41;&#44; and P2&#44; PBG and ALA in urine strictly normal&#46; Most carriers &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#44; 70&#46;5&#37;&#41; correspond to group P2&#44; i&#46;e&#46;&#44; they do not present biochemical abnormalities&#44; so that the study of these precursors in urine without a genetic or enzymatic analysis would fail to identify a carrier status&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">PBGD activity in red blood cells is decreased &#40;approximately 50&#37; from the normal value&#41; in all patients and asymptomatic carriers&#44; with no significant differences between the various groups &#40;A&#44; B&#44; P1 and P2&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Gene mutation was detected in all patients and carriers <span class="elsevierStyleItalic">PBGD</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a> These mutations were classified into 2 groups&#58; A&#44; <span class="elsevierStyleItalic">missense</span> mutation&#44; by amino acid change and&#44; consequently&#44; predictable residual activity of the mutant protein&#44; and B&#44; <span class="elsevierStyleItalic">non-missense</span> mutation&#44; including deletions&#44; <span class="elsevierStyleItalic">stop-codon</span>&#44; <span class="elsevierStyleItalic">splicing</span> defects and&#44; therefore&#44; non-predictable residual activity &#40;null mutation&#41;&#46; Overall&#44; patients showed &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>35&#41;&#44; 21 cases of null mutations &#40;60&#37;&#41; and 14 of <span class="elsevierStyleItalic">missense</span> mutations &#40;40&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A high proportion of null mutations was found in group B patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; &#40;6 patients&#44; 75&#37;&#41; in comparison with <span class="elsevierStyleItalic">missense</span> &#40;2 patients&#44; 25&#37;&#41;&#46; However&#44; group A showed &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41; 15 null mutations &#40;55&#37;&#41; compared to 12 <span class="elsevierStyleItalic">missense</span> &#40;45&#37;&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Among relatives &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>44&#41; there were 19 null mutation carriers &#40;43&#37;&#41; versus 24 &#40;54&#37;&#41; <span class="elsevierStyleItalic">missense</span>&#46; The group of carriers with biochemical abnormalities &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41; showed 7 null mutation carriers &#40;54&#37;&#41; versus 6 &#40;46&#37;&#41; <span class="elsevierStyleItalic">missense</span>&#46; Finally&#44; the group of carriers without biochemical abnormalities showed &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#41; 12 null mutations &#40;39&#37;&#41; versus 19 <span class="elsevierStyleItalic">missense</span> mutations &#40;61&#37;&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">This series includes all AIP patients seen at Hospital Cl&#237;nic of Barcelona&#44; with Catalonia as its area of influence&#44; with a population &#40;2014&#41; of 7&#46;5 million&#46; Most patients were not seen at first in the Hospital Cl&#237;nic&#44; as the start of the crisis is usually treated at the centre closest to the patient&#39;s home&#46; However&#44; once the period of initial severity had passed&#44; patients were referred to the Hospital Cl&#237;nic for definitive diagnosis and subsequent progression control&#46; Mortality in this series was 0&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">As reference site&#44; we have an approximate disease incidence indicator in our geographical area &#40;0&#46;25&#47;million inhabitants-year&#44; slightly higher than the calculated average in most European countries&#44; which is 0&#46;13&#47;million inhabitants-year&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">3</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">It is not possible to calculate the clinical penetrance of the disease without data on the general population&#39;s genetic defect prevalence&#46; A study in France measured PBGD activity in 3305 blood donors&#44; showing a prevalence of 0&#46;06&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">13</span></a> However&#44; no data are available in other European countries&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The high number of latent cases observed in our family study indicates that AIP&#39;s clinical penetrance is low&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> Our results show a large number of carriers in which the enzymatic and genetic deficiency do not incur in the development of the disease&#44; neither have an impact on biochemical alterations&#46; This shows that&#44; in most carriers&#44; liver homeostasis offsets PBGD deficiency without necessarily resulting in overproduction of heme precursors&#46; Only the concurrence of major precipitating factors may&#44; therefore&#44; lead to a metabolic pathway decompensation&#46; It is noteworthy that this decompensation with PBG and ALA accumulation may occur in other types of porphyria &#40;for example in the variegate porphyria&#41;&#44; where there is no <span class="elsevierStyleItalic">PBGD</span> gene mutation and yet&#44; it has never been described in non-carriers of porphyria&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Our series confirms that the autosomal dominant transmission disease is mainly developed in women &#40;94&#46;3&#37;&#41;&#46; This high proportion of females confirms observations made in other countries&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">4</span></a> It also confirms that the disease never develops before puberty&#44; and that there is a critical age band &#40;60&#37; of the cases in our series were &#60;30 years of age&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The possible explanation for women&#39;s greater susceptibility to AIP has not been fully figured out&#46; The human liver is sexually dimorphic with respect to the expression of numerous genes&#44; including <span class="elsevierStyleItalic">ALAS1</span>&#46; A complex network of transcription factors controls gene expression in the liver&#44; and numerous transcription factors are under the influence of the main hormonal axes&#44; which would explain sex susceptibility differences to <span class="elsevierStyleItalic">ALAS1</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a> induction&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In addition to hormonal factors&#44; our series highlights the role of stress&#44; surgical procedures with administration of drugs&#44; diets&#44; infections or self-medication as precipitating factors&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Delayed diagnosis is shown as a clear risk factor associated with PNS involvement&#44; which points to the need of being alert and requesting urgent porphyrins tests at the onset&#44; especially childbearing age women presenting unexplained abdominal pain&#44; hyponatremia or dark urine&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Fasting has shown to induce the <span class="elsevierStyleItalic">ALAS1</span> gene in the liver through the transcriptional coactivator PGC&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">14</span></a> The same mechanism would explain the beneficial effect of glucose treatment in acute attack&#44; and also the beneficial effect of a high-calorie diet as a protective factor&#46; Similarly&#44; various forms of stress&#44; such as traumatic&#44; mental or psychological can induce the <span class="elsevierStyleItalic">ALAS1</span> gene through stimulation of the adrenal-hypothalamic-pituitary axis&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Our series clearly illustrates how a majority of patients with AIP can achieve lasting clinical remission&#46; Lifestyle&#44; with minimization of stress&#44; body weight and a proper diet&#44; appears to be a major factor in determining disease remission course&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">However&#44; PBG and ALA urinary excretion after an acute attack is not normalized as in other types of acute porphyria &#40;e&#46;g&#46; variegate porphyria&#41;&#44; rather&#44; it remains high for long periods of time&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">15</span></a> The mechanisms involved in this non biochemical remission are unknown and are one of the possible factors contributing to the clinical recurrence&#46; The sustained <span class="elsevierStyleItalic">ALAS1</span> gene overactivity could be the cause of hepatic overproduction of PBG&#47;ALA&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Still&#44; long-term monitoring allows to observe a gradual decline in urinary concentrations of heme precursors in a significant number of patients during clinical remission&#46; The slope of this reduction is highly variable in our patients&#44; although in some cases it has been faster than that described by other authors&#44; who have calculated a PBG urinary half-life of 10&#46;6 years&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">15</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Recurrent patients constitute a major problem in the field of acute porphyria&#46; Periodic administration of hemin &#40;for example&#44; every 2&#8211;3 weeks&#41; during long periods results in avoiding severe crises&#44; yet&#44; it does not induce a clinical or biochemical remission&#46; In our series we have not been able to see a gradual decrease in the urinary concentrations of PBG&#47;ALA in this type of patients&#46; Recurrent features can be sustained in the liver by the transient effect of hemin on the <span class="elsevierStyleItalic">ALAS1</span> gene and the concomitant induction of heme oxygenase&#44; increasing heme degradation and quickly losing the negative <span class="elsevierStyleItalic">feedback</span> effect&#46; This hypothesis is perfectly adjusted to the rebound effect of PBG&#47;ALA in urine&#44; observed in our patients &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The long-term unsustainability of this treatment&#44; venous access problems&#44; or possible accumulation of iron in the liver have led in some cases to liver transplantation<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">8</span></a> or the design of gene therapy strategies&#44; presently under evaluation&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">16</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Although PBGD activity in peripheral blood is lower in recurrent cases&#44; these patients may present a more pronounced liver enzyme deficiency&#46; This could be explained by null type mutations in the <span class="elsevierStyleItalic">PBGD</span> gene&#44; which imply a lack of mutant protein compared to <span class="elsevierStyleItalic">missense</span> mutations&#44; which can allow a degree of residual activity&#46; Our data do not confirm this hypothesis&#44; because although null mutations are more common in recurrent group patients &#40;6 of 8&#41;&#44; 2 patients with <span class="elsevierStyleItalic">missense</span> &#40;R173W&#41; mutation had recurrent attacks&#46; The data&#44; however&#44; would support the hypothesis of a lower risk of recurrence in <span class="elsevierStyleItalic">missense</span> mutation cases&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">It is noteworthy that a patient in our series &#40;male with mutation R173W&#41;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a> could interrupt a prolonged treatment with hemin without recurrence of acute clinical symptoms or increased PBG&#47;ALA in urine&#46; Thus the possibility of leaving hepatic dysregulation in a natural way is shown by the administration of hemin&#47;induction of heme oxygenase&#47;<span class="elsevierStyleItalic">ALAS1</span> induction&#47;new hemin administration&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Thus&#44; factors associated with lifestyle&#44; right nutrition&#44; minimizing stress&#44; may not only be important in preventing acute attacks of AIP&#44; but also facilitate remission in cases of recurrence&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interests</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:11 [
        0 => array:3 [
          "identificador" => "xres625676"
          "titulo" => "Abstract"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Background and objectives"
            ]
            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Patients and method"
            ]
            2 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Results"
            ]
            3 => array:2 [
              "identificador" => "abst0020"
              "titulo" => "Conclusions"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec638836"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres625677"
          "titulo" => "Resumen"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abst0025"
              "titulo" => "Fundamento y objetivos"
            ]
            1 => array:2 [
              "identificador" => "abst0030"
              "titulo" => "Pacientes y m&#233;todo"
            ]
            2 => array:2 [
              "identificador" => "abst0035"
              "titulo" => "Resultados"
            ]
            3 => array:2 [
              "identificador" => "abst0040"
              "titulo" => "Conclusiones"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec638837"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Patients and method"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Results"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Conflict of interests"
        ]
        9 => array:2 [
          "identificador" => "xack210878"
          "titulo" => "Acknowledgements"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2014-05-12"
    "fechaAceptado" => "2014-06-26"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec638836"
          "palabras" => array:4 [
            0 => "Acute intermittent porphyria"
            1 => "Hemin"
            2 => "Porphobilinogen deaminase"
            3 => "Neurovisceral crisis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec638837"
          "palabras" => array:4 [
            0 => "Porfiria aguda intermitente"
            1 => "Hemina"
            2 => "Porfobilin&#243;geno deaminasa"
            3 => "Crisis neurovisceral"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Acute intermittent porphyria &#40;AIP&#41; is a rare disease that results from a deficiency of porphobilinogen deaminase&#44; the third enzyme of the heme biosynthetic pathway&#46; AIP carriers are at risk of presenting acute neurovisceral attacks associated with overproduction of heme-precursors in the liver&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We report the characteristics of all AIP patients attended in the Hospital Clinic of Barcelona during the years 1993&#8211;2013 and their long-term follow-up&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Thirty-five AIP patients &#40;33 women&#44; 2 men&#41; experienced acute attacks&#46; Treatment with hemin resolved the acute neurovisceral crisis in all cases&#46; Nine patients presented peripheral neuropathy and persistent sequelae&#46; Long-term follow-up allowed classifying the patients into groups&#58; A&#44; patients with acute symptoms during 1&#8211;2 years and subsequent long-lasting clinical remission &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41; or a few sporadic crises &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&#44; and B&#44; patients with recurrent attacks requiring chronic administration of hemin &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#46; In a majority of the patients of group A&#44; the urinary excretion of heme-precursors decreased gradually over time&#46; However&#44; the chronic hemin regime did not induce a decline of urinary heme-precursors in the patients of group B&#46; Additionally&#44; we identified 44 asymptomatic AIP carriers&#44; most &#40;70&#46;5&#37;&#41; with normal values of heme-precursors in urine&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A majority of the AIP patients of our series achieved a long-lasting clinical remission&#46; A minority &#40;23&#37;&#41; presented recurrent attacks that required chronic hemin infusions without feasible interruption and without long-term biochemical remission&#46; The type of mutation within the porphobilinogen deaminase gene and also life-style related factors may determine remission time-course&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Patients and method"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Fundamento y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La porfiria aguda intermitente &#40;PAI&#41; es una enfermedad causada por un defecto en la enzima porfobilin&#243;geno deaminasa que cataliza la tercera etapa de s&#237;ntesis del hemo&#46; Los portadores pueden presentar ataques neuroviscerales agudos tras sobreproducci&#243;n hep&#225;tica de precursores del hemo&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se presentan las caracter&#237;sticas de todos los pacientes con PAI atendidos en el Hospital Cl&#237;nic de Barcelona entre los a&#241;os 1993-2013&#44; y su seguimiento a largo plazo&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Treinta y cinco pacientes con PAI &#40;33 mujeres y 2 varones&#41; presentaron ataques agudos neuroviscerales&#46; El tratamiento con hemina resolvi&#243; el cuadro agudo en todos los casos&#46; Nueve pacientes presentaron polineuropat&#237;a y secuelas persistentes&#46; El seguimiento permiti&#243; clasificar a los pacientes en&#58; A&#44; con sintomatolog&#237;a aguda durante 1-2 a&#241;os y posterior remisi&#243;n duradera &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41; o bien alguna crisis puntual &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&#44; y B&#44; con ataques recurrentes que requirieron administraci&#243;n cr&#243;nica de hemina &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#46; En la mayor&#237;a de los pacientes del grupo A la concentraci&#243;n urinaria de precursores del hemo fue disminuyendo progresivamente&#44; mientras que en el grupo B esta se mantuvo elevada sin descenso observable a largo t&#233;rmino&#46; Adicionalmente&#44; el estudio familiar permiti&#243; identificar 44 portadores asintom&#225;ticos&#44; la mayor&#237;a &#40;70&#44;5&#37;&#41; con valores normales de precusores del hemo en orina&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Una mayor&#237;a de pacientes con PAI de nuestra serie logr&#243; una remisi&#243;n cl&#237;nica duradera&#46; Una minor&#237;a presenta ataques recurrentes&#44; sin que el tratamiento cr&#243;nico con hemina haga factible su interrupci&#243;n ni induzca remisi&#243;n bioqu&#237;mica a largo plazo&#46; El tipo de mutaci&#243;n en el gen de la porfobilin&#243;geno deaminasa&#44; y tambi&#233;n factores asociados al estilo de vida&#44; pueden determinar el curso de la remisi&#243;n&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Fundamento y objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Pacientes y m&#233;todo"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Herrero C&#44; Badenas C&#44; Aguilera P&#44; To-Figueras J&#46; Porfiria aguda intermitente&#58; seguimiento a largo t&#233;rmino de 35 pacientes&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;145&#58;332&#8211;337&#46;</p>"
      ]
    ]
    "multimedia" => array:6 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1275
            "Ancho" => 1624
            "Tamanyo" => 101094
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Long-term progression of urinary concentration of porphobilinogen &#40;PBG&#41; and delta-aminolevulinic acid &#40;ALA&#41; in one patient in group A&#46; Concentration of PBG and ALA expressed in mmol&#47;mol creatinine&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1205
            "Ancho" => 1635
            "Tamanyo" => 206108
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Long-term progression of urinary concentration of porphobilinogen &#40;PBG&#41; and delta-aminolevulinic acid &#40;ALA&#41; in one patient in group B&#44; under maintenance treatment with hemin&#46; PBG and ALA concentration expressed in mmol&#47;mol creatinine&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1072
            "Ancho" => 1559
            "Tamanyo" => 139937
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Short term oscillation of porphobilinogen &#40;PBG&#41; and delta-aminolevulinic acid &#40;ALA&#41; concentration in a group B patient after administration of hemin&#46; PBG and ALA concentration expressed in mmol&#47;mol creatinine&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1389
            "Ancho" => 1577
            "Tamanyo" => 133653
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Long-term progression of porphobilinogen &#40;PBG&#41; and delta-aminolevulinic acid &#40;ALA&#41; concentration in one group B patient&#44; during the period of treatment with hemin &#40;1&#8211;8 years&#41; and after stopping the treatment &#40;8&#8211;10 years&#41;&#46; PBG and ALA concentration expressed in mmol&#47;mol creatinine&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">A&#58; sporadic crises&#59; B&#58; recurrent crises&#59; PBGD&#58; porphobilinogen deaminase enzyme&#59; P1&#58; with a PBG and ALA increase in urine&#59; P2&#58; normal porphobilinogen and delta-aminolevulinic acid in urine&#59; CNS&#58; central nervous system&#59; PNS&#58; peripheral nervous system&#59; ANS&#58; autonomic nervous system&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Patients</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Carriers</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27 &#40;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;29&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31 &#40;70&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Average age &#40;ends&#41; at the time of the study&#44; years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">41&#46;35 &#40;22&#8211;76&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42&#46;7 &#40;22&#8211;76&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;22&#8211;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43&#46;4 &#40;23&#8211;84&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;28&#8211;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#46;8 &#40;23&#8211;84&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Female</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33 &#40;94&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Male</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age at first crisis &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28&#46;2 &#40;17&#8211;46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#46;4 &#40;17&#8211;39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29&#46;8 &#40;21&#8211;46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>15&#8211;20 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;11&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>20&#8211;30 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;51&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>30&#8211;40 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;34&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>40&#8211;50 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;2&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Isolated ANS involvement</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 &#40;74&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">ANS&#44; PNS and CNS involvement</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;25&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">PBGD activity in red blood cells</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">63&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">61&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Mutations</span> PBGD missense&#47;<span class="elsevierStyleItalic">null</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#47;21 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#47;15 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;6 &#40;0&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&#47;19 &#40;1&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;7 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;19 &#40;1&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Follow up</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;39 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;39 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;13 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8211;31 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;31 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8211;14 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1026502.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">General characteristics of the group of patients and relatives studied&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Data expressed as n &#40;&#37;&#41;&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stress and&#47;or psychiatric disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Surgery under anaesthesia<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11 &#40;31&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Calorie diet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Menstruation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">More than one factor<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20 &#40;57&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1026501.png"
              ]
            ]
          ]
          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Surgery&#44; childbirth&#44; abortion&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Two factors in 10 cases&#59; 3 factors in 10 cases&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">First crisis triggers&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:16 [
            0 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Porphyrias"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Puy"
                            1 => "L&#46; Gouya"
                            2 => "J&#46;C&#46; Deybach"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(09)61925-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2010"
                        "volumen" => "375"
                        "paginaInicial" => "924"
                        "paginaFinal" => "937"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20226990"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute intermittent porphyria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "B&#46; Grandchamp"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-2007-1007136"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Liver Dis"
                        "fecha" => "1998"
                        "volumen" => "18"
                        "paginaInicial" => "17"
                        "paginaFinal" => "24"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9516674"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The incidence of inherited porphyrias in Europe"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "G&#46; Elder"
                            1 => "P&#46; Harper"
                            2 => "M&#46; Badminton"
                            3 => "S&#46; Sandberg"
                            4 => "J&#46;C&#46; Deybach"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10545-012-9544-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Inherit Metab Dis"
                        "fecha" => "2013"
                        "volumen" => "36"
                        "paginaInicial" => "849"
                        "paginaFinal" => "857"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23114748"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prognosis of acute porphyria&#58; occurrence of acute attacks&#44; precipitating factors&#44; and associated diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Kauppinen"
                            1 => "P&#46; Mustajoki"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Medicine &#40;Baltimore&#41;"
                        "fecha" => "1992"
                        "volumen" => "71"
                        "paginaInicial" => "1"
                        "paginaFinal" => "13"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An analysis of 112 acute porphyric attacks in Cape Town South Africa&#58; evidence that acute intermittent porphyria and variegate porphyria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;J&#46; Hift"
                            1 => "P&#46;N&#46; Meissner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Medicine &#40;Baltimore&#41;"
                        "fecha" => "2005"
                        "volumen" => "84"
                        "paginaInicial" => "48"
                        "paginaFinal" => "60"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute porphyrias&#58; pathogenesis of neurological manifestations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "U&#46;A&#46; Meyer"
                            1 => "M&#46;M&#46; Schuurmans"
                            2 => "R&#46;L&#46; Lindberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-2007-1007139"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Liver Dis"
                        "fecha" => "1998"
                        "volumen" => "18"
                        "paginaInicial" => "43"
                        "paginaFinal" => "52"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9516677"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Outside the box&#58; genomic approach to acute porphyria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46; Thunell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Physiol Res"
                        "fecha" => "2006"
                        "volumen" => "55"
                        "paginaInicial" => "43"
                        "paginaFinal" => "66"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver transplantation as a cure for acute intermittent porphyria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Z&#46;F&#46; Soonawalla"
                            1 => "T&#46; Orug"
                            2 => "M&#46;N&#46; Badminton"
                            3 => "G&#46;H&#46; Elder"
                            4 => "J&#46;M&#46; Rhodes"
                            5 => "S&#46;R&#46; Bramhall"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(04)15646-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2004"
                        "volumen" => "363"
                        "paginaInicial" => "705"
                        "paginaFinal" => "706"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15001330"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "European specialist porphyria laboratories&#58; diagnostic strategies&#44; analytical quality&#44; clinical interpretation&#44; and reporting as assessed by an external quality assurance program"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;K&#46; Aarsand"
                            1 => "J&#46;H&#46; Villanger"
                            2 => "E&#46; St&#248;le"
                            3 => "J&#46;C&#46; Deybach"
                            4 => "J&#46; Marsden"
                            5 => "J&#46; To-Figueras"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1373/clinchem.2011.170357"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Chem"
                        "fecha" => "2011"
                        "volumen" => "57"
                        "paginaInicial" => "1514"
                        "paginaFinal" => "1523"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21937752"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic and biochemical characterization of 16 acute intermittent porphyria cases with a high prevalence of the R173W mutation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; To-Figueras"
                            1 => "C&#46; Badenas"
                            2 => "C&#46; Carrera"
                            3 => "C&#46; Mu&#241;oz"
                            4 => "M&#46; Mila"
                            5 => "M&#46; Lecha"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10545-006-0344-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Inherit Metab Dis"
                        "fecha" => "2006"
                        "volumen" => "29"
                        "paginaInicial" => "580"
                        "paginaFinal" => "585"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16817012"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Late diagnosis of a case of acute intermittent porphyria in the ICU"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;J&#46; Betbes&#233;"
                            1 => "L&#46; Zapata"
                            2 => "C&#46; Mart&#237;nez-Br&#250;"
                            3 => "C&#46; Herrero"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.medin.2009.09.009"
                      "Revista" => array:5 [
                        "tituloSerie" => "Med Intensiva"
                        "fecha" => "2010"
                        "volumen" => "34"
                        "paginaInicial" => "358"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19939505"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prognosis of polyneuropathy associated to intermittent acute porphyria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Vall&#232;s"
                            1 => "J&#46; Benito"
                            2 => "R&#46; Pelayo"
                            3 => "J&#46; Vidal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Med Clin &#40;Barc&#41;"
                        "fecha" => "2011"
                        "volumen" => "137"
                        "paginaInicial" => "191"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute intermittent porphyria&#58; prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Nordmann"
                            1 => "H&#46; Puy"
                            2 => "V&#46; da Silva"
                            3 => "S&#46; Simonin"
                            4 => "A&#46;M&#46; Robreau"
                            5 => "C&#46; Bonaiti"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Intern Med"
                        "fecha" => "1997"
                        "volumen" => "242"
                        "paginaInicial" => "213"
                        "paginaFinal" => "217"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9350165"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Handschin"
                            1 => "J&#46; Lin"
                            2 => "J&#46; Rhee"
                            3 => "A&#46;K&#46; Peyer"
                            4 => "S&#46; Chin"
                            5 => "P&#46;H&#46; Wu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cell.2005.06.040"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell"
                        "fecha" => "2005"
                        "volumen" => "122"
                        "paginaInicial" => "505"
                        "paginaFinal" => "515"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16122419"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Urinary excretion of porphyrins&#44; porphobilinogen and &#948;-aminolaevulinic acid following an attack of acute intermittent porphyria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;T&#46; Marsden"
                            1 => "D&#46; Rees"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jclinpath-2012-201367"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Pathol"
                        "fecha" => "2014"
                        "volumen" => "67"
                        "paginaInicial" => "60"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23908454"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates&#58; a potential therapy for acute intermittent porphyria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Pa&#241;eda"
                            1 => "E&#46; Lopez-Franco"
                            2 => "C&#46; Kaeppel"
                            3 => "C&#46; Unzu"
                            4 => "A&#46;G&#46; Gil-Royo"
                            5 => "D&#46; D&#8217;Avola"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/hum.2013.166"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hum Gene Ther"
                        "fecha" => "2013"
                        "volumen" => "24"
                        "paginaInicial" => "1007"
                        "paginaFinal" => "1017"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24070415"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack210878"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0220" class="elsevierStylePara elsevierViewall">The authors want to thank the Porphyria&#39;s Unit&#39;s nursing staff at the Hospital Cl&#237;nic of Barcelona for the many years of continued support&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/23870206/0000014500000008/v1_201604030058/S238702061600108X/v1_201604030058/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "43310"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/23870206/0000014500000008/v1_201604030058/S238702061600108X/v1_201604030058/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702061600108X?idApp=UINPBA00004N"
]