PICO questions and DELPHI methodology for improving the management of patients with acute hepatic porphyria.

BACKGROUND: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients. MATERIAL AND METHODS: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP. RESULTS: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP. CONCLUSIONS: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP.

Persistir y no desistir: diagnosticando un caso de porfiria aguda intermitente / Persist and do not give up: diagnosing a case of acute intermittent porphyria

A young woman with a history of asthma and anxiety-depressive syndrome, with poor adherence to treatment in long follow-up by Psychiatry and Family Medicine. She consulted for persistent abdominal pain refractory to conventional analgesia, associated with hypertension, hyponatremia, and progressive muscle weakness. It was performed a first Hoesch test which was positive; however, the study of porphyrins in blood and urine was inconclusive. On the other hand, she presented an acute respiratory failure requiring transfer to the ICU. A second Hoesch test was repeated, remaining positive, in addition to the presence of an increase in porphobilinogen in 24-hour urine and delta-aminolevulinic acid. Genetic study was performed, being compatible with acute intermittent porphyria. Treatment with carbohydrates and hemin was started with an adequate response. Approval of givosiran (RNA interference drug) has been requested. The patient has shown clinical improvement. Due to functional deterioration, she required rehabilitation support. (AU)

Mujer joven con antecedentes de asma y síndrome ansioso-depresivo con escasa adherencia al tratamiento, en seguimiento por Psiquiatría y Médico de Familia desde hace años. Consultó por dolor abdominal persistente y refractario a analgesia convencional, junto con hipertensión, hiponatremia y debilidad muscular progresiva. Se realizó un primer test de Hoesch que fue positivo, aunque el estudio inicial de porfirinas en sangre y orina no fue concluyente. Posteriormente presentó insuficiencia respiratoria aguda, precisando traslado a UCI. Se repitió el test de Hoesch, nuevamente positivo, además de hallar incremento de porfobilinógeno en orina de 24 horas y de ácido delta-aminolevulínico. El estudio genético fue compatible con porfiria aguda intermitente. Recibió tratamiento con carbohidratos y hemina con adecuada respuesta. Está pendiente de aprobación de givosiran (fármaco ARN de interferencia). Ha evolucionado favorablemente, precisando soporte rehabilitador por marcado deterioro funcional. (AU)

Síndromes de sobrecrecimiento relacionados con PIK3CA (PROS): Conocimiento nuevo de enfermedades conocidas / PIK3CA-related overgrowth spectrum (PROS): new insight in known diseases

Los síndromes de sobrecrecimiento relacionados con la fosfatidilinositol-4,5-bifosfato 3-cinasa (PI3K), se agrupan bajo el concepto de PIK3CA-related overgrowth spectrum (PROS). Son un grupo heterogéneo de entidades, considerado una enfermedad minoritaria (ORPHA: 530313), que combina la presencia de malformaciones vasculares con el sobrecrecimiento segmentario de algunas partes del cuerpo. Todas estas enfermedades están causadas por mutaciones en el gen que codifica la subunidad alfa de la PI3K. Estas mutaciones son somáticas y tienen lugar durante la embriogénesis. Dependiendo del momento del desarrollo embrionario que se produzcan y a qué hoja precursora afecten, el fenotipo será muy distinto, desde síndromes con extensa afectación a formas aisladas. A pesar de que existen unos criterios clínicos, la identificación de la mutación mediante realización de una biopsia, aunque compleja, confirma el diagnóstico. El objetivo del presente trabajo es revisar los aspectos fisiopatológicos, clínicos, diagnósticos y terapéuticos del PROS, con el fin de optimizar su identificación. (AU)

The overgrowth syndromes related to phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) are grouped under the concept of PROS (PIK3CA-related overgrowth spectrum). It is a heterogeneous group of diseases, considered a rare disease (ORPHA: 530313), which combines the presence of vascular malformations with segmental overgrowth of some parts of the body. All these diseases are caused by mutations in the gene that encodes for the alpha subunit of PI3K. These mutations are somatic and take place during the embryonic stage. Depending on the stage of embryonic development and the affected germ layers, the phenotype will be very different, from syndromes with extensive involvement to isolated forms. Although there are clinical criteria, identification of the mutation by biopsy, although complex, confirms the diagnosis. The objective of the present study is to review the pathophysiological, clinical, diagnostic, and therapeutic aspects of PROS, in order to optimize its identification. (AU)

[PIK3CA-related overgrowth spectrum (PROS): new insight in known diseases]. / Síndromes de sobrecrecimiento relacionados con PIK3CA (PROS): Conocimiento nuevo de enfermedades conocidas.

The overgrowth syndromes related to phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) are grouped under the concept of PROS (PIK3CA-related overgrowth spectrum). It is a heterogeneous group of diseases, considered a rare disease (ORPHA: 530313), which combines the presence of vascular malformations with segmental overgrowth of some parts of the body. All these diseases are caused by mutations in the gene that encodes for the alpha subunit of PI3K. These mutations are somatic and take place during the embryonic stage. Depending on the stage of embryonic development and the affected germ layers, the phenotype will be very different, from syndromes with extensive involvement to isolated forms. Although there are clinical criteria, identification of the mutation by biopsy, although complex, confirms the diagnosis. The objective of the present study is to review the pathophysiological, clinical, diagnostic, and therapeutic aspects of PROS, in order to optimize its identification.

Perfil de pacientes con enfermedades minoritarias en Galicia. Perspectiva desde la medicina interna / Clinical profile of patients with rare diseases. An approach from Internal Medicine

Objetivos: Las enfermedades minoritarias constituyen un grupo heterogéneo de patologías de baja prevalencia, con un origen genético en la mayoría de los casos y frecuentemente asociadas a un retraso en su diagnóstico y notable morbi-mortalidad. Conocer las características clínicas y el grado de complejidad asistencial de los pacientes con enfermedades minoritarias que acuden a las consultas de medicina interna en Galicia podría facilitar una atención más eficaz y eficiente. Material y métodos: Estudio epidemiológico, transversal y multicéntrico en pacientes con enfermedad de baja prevalencia ≥ 18 años atendidos en las consultas y unidades específicas de medicina interna en Galicia hasta el 31 de Diciembre de 2020. Se obtuvieron de cada centro el número de pacientes atendidos según la patología, la media en años desde la aparición de los síntomas, número de comorbilidades, número de visitas anuales al centro y a otros especialistas, número de tratamientos (incluidos aquellos de alto impacto económico), grado de deterioro cognitivo y estimación del nivel de dependencia. Resultados: Se analizaron los indicadores de seis centros correspondientes a seis áreas sanitarias de Galicia, representando a un total de 324 pacientes, con una edad media de 41,3 ±15,8 años. Los tres principales grupos de patologías atendidas fueron por este orden las enfermedades genéticas raras, los errores innatos del metabolismo y las enfermedades neurológicas raras. El retraso medio en el diagnóstico fue de 4,8 ±7,9 años y un 34,17% de los pacientes tardaron 5 o más años en tener una confirmación diagnóstica. Este grupo de mayor retraso diagnóstico presenta menor puntuación en la escala de dependencia de Barthel y 1,75 veces mayor utilización de recursos sanitarios (consultas a medicina interna y otras especialidades). El 11,75% de los pacientes presentan un nivel de dependencia severa o total y el 9,9%, un bajo coeficiente intelectual. Conclusiones: ... (AU)

Objectives: Rare diseases (RD) constitute a heterogeneous group of low prevalence conditions, with genetic origin in most cases and frequently associated with a delay in their diagnosis and notable morbidity and mortality. Knowing the clinical profile and the complexity degree of patientswith RD who attend internal medicine units in Galicia could facilitate more effective and efficient care settings. Methods: Epidemiological, cross-sectional and multicenter study in patients with low prevalence diseases ≥ 18 years attending the outpatients departments and specific units of internal medicine in Galicia up to December 31, 2020. Data were collected on the number of patients treatedregarding their condition at each center, the average age at disease onset, number of comorbidities, number of annual visits to the center and other specialists, number of treatments (including those with a high economicimpact), degree of cognitive impairment and assessment of the degree of autonomy. Results: We analyzed data from six participating centers (from six healthareas of Galicia), representing a total of 324 patients, with a mean age of 41.3 ±15.8 years. The three main groups of pathologies treated were, in this order, rare genetic diseases, innate errors of metabolism and rareneurological diseases. The mean delay in diagnosis was 4.8 ±7.9 years and 34.17% of patients took 5 or more years to have a diagnostic confirmation. This group with the longest diagnostic delay has a lower scoreon the Barthel dependency scale and 1.75 times greater use of health resources (consultations with internal medicine and other specialties). 11.75% of the patients present a level of severe or total dependence and 9.9%, a low IQ. Conclusions: Despite their low average age, patients with minority diseases treated in internal medicine services present a high complexity of care derived from the number of comorbidities, visits to consultations, the need for hospital admissions and polypharmacy... (AU)

Medical management of haemorrhagic hereditary telangiectasia in adult patients. / Tratamiento de la telangiectasia hemorrágica hereditaria en el paciente adulto.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited Rare Disease that causes a systemic anomalous vascular overgrowth. The approach and follow-up of these patients should be from multidisciplinary units. Its diagnosis is carried out according to Curaçao clinical Criteria. Telangiectasia in the nasal mucosa cause recurrent epistaxis, the main symptom of HHT and difficult to control. The three types of hepatic shunting, hepatic artery to hepatic vein, hepatic artery to portal vein or to portal vein to hepatic vein, can cause high-output heart failure, portal hypertension or porto-systemic encephalopathy, respectively. These types of vascular involvement can be established using computerised tomography. Pulmonary arteriovenous fistula should be screened for all HHT patients by contrast echocardiography. The main objective is to review the management of epistaxis, liver and lung involvement of the adult patient with HHT.

Computerized registry of patients with hemorrhagic hereditary telangiectasia (RiHHTa Registry) in Spain: Objectives, methods, and preliminary results. / Registro informatizado de la telangiectasia hemorrágica hereditaria (Registro RiHHTa) en España: objetivos, métodos y resultados preliminares.

INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is a rare disease with autosomal dominant inheritance that causes systemic vascular affectation. MATERIAL AND METHOD: After development a multicentric Spanish national registry, called RiHHTa, main clinical manifestations and diagnostic procedures of the first patients introduced are described. RESULTS: 141 patients were included, of which 91 (64.5%) were women. The mean age at diagnosis was 42 years. Mutations in the ACVRL1 gene predominated over the ENG gene. The initial symptom was recurrent epistaxis in 130 (92.2%) patients and in three (2.1%), brain abscess. Pulmonary arteriovenous (AV) fistula were detected in 36 (45%) of the 79 patients who underwent thoracic CT angiography. The contrast echocardiography detected very few bubbles (grade I) or none, in 36 (45%) of these 79 affected patients. In 43 (67.2%) of the 64 patients with an abdominal CT angiography, hepatic vascular malformations were detected, mostly telangiectasias, AV and arterio-portal fistula, and extrahepatic in 14 (10%) subjects. More than half of the patients were screened for the presence of brain arteriovenous malformations which was found in 3.9% of them. The upper part of the intestinal tube was the most (95%) affected region. CONCLUSION: The RiHHTa Registry allows improving the management of patients with HHT. An inadequate use of thoracic CT angiography and the usefulness of abdominal CT angiography has been detected in order to define subtypes of hepatic vascular involvement and detect extrahepatic vascular involvement.