Hipofosfatasemia crónica persistente de causa no determinada y su repercusión músculo-esquelética / Persistent hypophosphatasemia and its musculoskeletal repercussion

La fosfatasa alcalina baja o hipofosfatasemia, ya sea debida a causas genéticas (hipofosfatasia) o secundarias, presenta correlato clínico. Nuestro objetivo es estimar la prevalencia de hipofosfatasemia crónica persistente y describir sus hallazgos osteometabólicos. Se realizó una búsqueda electrónica de afiliados adultos al Hospital Italiano de Buenos Aires, entre 2013 y 2017, con al menos 2 determinaciones de fosfatasa alcalina igual a 30 UI/l o menor y ninguna mayor de 30 UI/l (rango de referencia 30-100 UI/l). Se excluyeron aquellos con causas secundarias diagnosticadas y se analizaron los correlatos clínico y bioquímico. Se detectó hipofosfatasemia crónica persistente en 78 de 105.925, 0,07% (0,06-0,09) de los afiliados. Solo uno fue excluido por tener causa secundaria. Eran 61,1% mujeres de 44 (34-56) años, fosfatasa alcalina 24 (20-27) UI/L, fosfatemia 4,1 (3,8-4,6) mg/dl. Se observaron osteoartritis, calcificaciones vasculares y fracturas, menos frecuentemente litiasis renal, calcificación del ligamento longitudinal común anterior, pérdida dental y convulsiones. El 63,6% tenían al menos una de las características clínico-radiológicas evaluadas, pero en solo 5,2% fue mencionado el diagnóstico de hipofosfatasemia en la historia clínica. La densitometría evidenció algún grado de afección (osteopenia u osteoporosis) en 76,2%. Se constataron 19 fracturas, con predominio en radio. La prevalencia de hipofosfatasemia fue similar a lo previamente reportado. El reconocimiento fue bajo; sin embargo, se observaron variadas manifestaciones músculo-esqueléticas, similares a las descriptas en la hipofosfatasia del adulto, por lo cual ­ante una hipofosfatasemia sin causa secundaria­ se sugiere considerar este diagnóstico. (AU)

Low alkaline phosphatase (ALP) or hypophosphatasemia either due to genetic (hypophosphatasia) or secondary causes, presents a clinical correlate. Our objectives are to estimate the prevalence of persistent hypophosphatasemia and to describe the clinical findings. We performed a search using the electronic medical records of the members of the Hospital Italiano de Buenos Aires health care system, between 2013 and 2017. Adult members with ≥ 2 ALP ≤ 30 IU/l, no ALP >30 IU/l (normal range 30-100 UI/l) and without diagnosed secondary causes were analyzed. Persistent hypophosphatasemia was detected in 78 of 105.925, 0.07% (0.06-0.09) of members. Only one was excluded due to a secondary cause, 61.1% were women, 44 (34-56) year-old, ALP 24 (20-27) IU/l and phosphatemia 4.1 (3.8-4.6) mg/dl. Osteoarthritis, vascular calcifications and fractures were detected, and nephrolithiasis, DISH (Diffuse idiopathic skeletal hyperostosis), tooth loss, and seizures were less frequently observed. At least one of the mentioned characteristics were present in 63.6 %, but only 5.2% had hypophosphatasemia registered in their clinical record. Densitometry showed osteopenia or osteoporosis in 76.2%. There were 19 fractures, most of them in radius. The prevalence of hypophosphatasemia was similar to what has been previously reported. Hypophosphatasemia finding in medical records was low, but far from being asymptomatic, clinical manifestations were observed. In the presence of hypophosphatasemia without a secondary cause, adult hypophosphatasia should be uspected. (AU)

Hipofosfemia en recién nacidos prematuros: un trastorno bimodal / Hypophosphatemia in preterm infants: a bimodal disorder

Las estrategias nutricionales para prematuros extremos con alto aporte de proteínas, han mostrado alteraciones metabólicas con hipofosfemia precoz, especialmente en el grupo de pacientes con restricción de crecimiento intrauterino (Rein). También se presenta hipofosfemia tardía, característica de la enfermedad metabólica ósea. En este artículo se revisan y actualizan conceptos en relación a la fisiopatología del metabolismo del fósforo en recién nacidos prematuros y uso de parenterales precoces en el contexto de enfermedad metabólica ósea. Los artículos fueron identificados en base de datos electrónicas como Pubmed y Rima. Fueron incluidos artículos en inglés y español. Fueron filtrados por título y resumen. La literatura actual propone diversas estrategias de nutrición precoz que permitan asegurar una adecuada cantidad de nutrientes para continuar con el crecimiento y desarrollo extrauterino. En pacientes con nutrición parenteral pero con diferentes aportes de fósforo, o relación calcio: fósforo inadecuada, a mayor contenido de aminoácidos, se presenta hipofosfemia, hipercalcemia, hipomagnesemia, hipokalemia e hiperglicemia, especialmente en casos de Rein. Estas alteraciones se asocian a prolongación de ventilación mecánica, mayor riesgo de displasia broncopulmonar y aumento de sepsis tardía. La hipofosfemia tardía, descrita ya hace muchos años, se presenta con normocalcemia y aumento de fosfatasas alcalinas, en la enfermedad metabólica ósea del prematuro, con alteración de la mineralización en distintos grados, secundaria a un inadecuado aporte de este mineral para los altos requerimientos de estos pacientes. Esta presentación de hipofosfemia precoz y tardía en el prematuro alerta sobre el control oportuno de fosfemia para ajustar el aporte nutricional. En el prematuro con nutrición parenteral precoz, el control en conjunto con la calcemia en la primera semana de vida, especialmente en Rein, permite tratar la hipofosfemia y prevenir sus complicaciones. En hipofosfemia tardía, el seguimiento semanal o quincenal desde las 4 semanas a los prematuros con riesgo, permite lograr un aporte óptimo de minerales.

New nutritional approaches to treat extreme premature babies have demonstrated relevant eviden ce of metabolic disturbances with early hypophosphatemia, especially in patients with intrauterine growth restriction (IUGR). They have shown late hypophosphatemia, as well, which is characteristic in the metabolic bone disease. A sytematic search of literature describing metabolic disturbances of phosphorus in preterm newborns is presented, related to the use of early parenteral nutrition and also in the context of metabolic bone disease. The articles were gathered from electronic data bases, such as PubMed and Rima. We include articles in english and spanish which were selected by titles and abstracts. Several strategies for early nutrition have been proposed in order to ensure an adequate amount of nutrients to accomplish the development and growth of preterm babies. Patients with parenteral nutrition support with different doses of phosphate, or inadequate calcium phosphate relation, or an increased amino acid content, may present hypophosphatemia, hypercalcemia, hy pomagnesemia, hypokalemia and hyperglycemia, all of these are additionally noteworthy in the pre sence of intrauterine growth restriction. Furthermore, said alterations are associated with prolonged mechanical ventilation, as well as bronchopulmonary dysplasia and increase in late onset sepsis. The late hypophosphatemia, described several years ago, arises as normocalcemia and as an increment of alkaline phosphatases in the metabolic bone disease in preterm babies, and also with an inadequate mineralization in different grades, secondary to an inadequate supply due to high nutritional requi rements in these patients. When early or late hypophosphatemia appears in preterm babies, it shall require timely control of phosphemia and will need to adjust the nutritional intake in order to correct it. In case of preterm babies with early parenteral nutrition it will also need a control of calcemia in the first week of birth, especially if those belonging to the IUGR group. Adjustment must be made along with metabolic follow up, as well. In late hypophosphatemia, a weekly or every two weeks fo llow up will be a must for all preterm babies in risk and they should be given supplements to get an optimum mineral supply.

Síndrome de realimentación: el diagnóstico pendiente / Refeeding syndrome: the pending diagnosis

Introducción: El síndrome de realimentación (SR) puede definirse como el conjunto de alteraciones metabólicas desencadenadas tras la rápida reintroducción del soporte nutricional en pacientes severamente desnutridos o con ayuno prolongado. Puede tener repercusiones clínicas, neurológicas y cardiológicas. La hipofosfatemia es el fenómeno predominantemente asociado con el SR. Paciente masculino de 68 años con antecedentes de tabaquismo, EPOC y depresión. Ingresa a UTI por sepsis a foco respiratorio severamente desnutrido (por Valoración Global Subjetiva), con IMC 14.6 kg/m². Inicia nutrición enteral (NE) al 30% de sus requerimientos por riesgo de SR con P sérico basal de 3,9 mg/dl. Al 2do día no se dosa P ni Mg séricos, pero sí se observa K dentro de parámetros normales. Se progresa NE al 50%, y se observa al 3ro°día una disminución significativa del P a 2,1 mg/dl, llegando a 1,9 mg/dl el 4to°día, sin haber progresado aportes (K y Mg en descenso pero dentro de parámetros normales). Se carga al 4to°día con una ampolla de fosfato de potasio, evolucionando favorablemente. Objetivo: Destacar la importancia de prevenir el SR. Discusión: Se observó la repercusión bioquímica característica del SR. El momento de detección de la hipofosfatemia significativa (3ro°día) coincide con el promedio general visto en otros estudios. No hubieron signos clínicos, probablemente porque el P no tuvo un valor crítico. Como terapéutica, se utilizó la lenta progresión de aportes y la corrección de P fue tardía. Podría haber sido adecuada la suplementación de tiamina previo inicio de NE

Introduction: The refeeding syndrome (SR) can be defined as the metabolic alterations developed after a rapid nutrition repletion (oral, enteral, as well as parenteral feeding) of severely malnourished patients. It can have clinical, neurological and cardiological effects. Hypophosphatemia is the predominantl phenomenon associated with SR. A 68-year-old male patient with a history of smoking, COPD, and depression, who is admitted in ICU severely malnourished (Subjetive Global Assesment) due to sepsis at a respiratory focus, with a BMI of 14.6 kg / m². The patient initiates enteral nutrition (NE) at 30% of its requirements due to risk of SR, with baseline serum P value of 3.9 mg/dl. At day 2, no serum P or Mg is given, but K is observed within normal parameters. NE is progressed up to 50%, and a significant decrease of P at 2.1 mg/dl is observed at day 3, reaching 1.9 mg/dl at day 4, with no progress (K and Mg in decline but within normal parameters). He is loaded at day 4 with a potassium phosphate ampoule, evolving favorably. Objective: Highlighting the importance of preventing SR. Discussion: The characteristic biochemical repercussion of SR was observed. The moment of detection of significant hypophosphatemia (day 3) coincides with the general average seen in other studies. There were no clinical signs, probably because P didn´t have a critical value. As therapy, the slow progression of caloric contributions was used, and the correction of P was late. Thiamine supplementation may have been adequate prior to initiation of NE.

Hypophosphataemic rickets/osteomalacia: A descriptive analysis.

Background & objectives: Hypophosphataemic rickets/osteomalacia (HRO) is an uncommon metabolic bone disorder which affects all ages and either sex. It is characterized by low concentration of serum phosphate levels leading to impairment of mineralization of bone matrix with variable aetiology. We present clinical profile and treatment outcome of 17 patients of HRO. Methods: Seventeen consecutive patients (8 were < 18 yr of age, with median age of presentation being 27.5 yr) of HRO who came to the department of Endocrinology in a tertiary care hospital in north India from January 2000 to December 2006 were included in the present study. Their aetiology, clinical features, biochemical parameters, radiographic features, treatment and outcome were analyzed. Results: HRO was commoner in females (70.5%) with positive family history observed in 6 (35.3%) patients. Common presenting features were short stature (58.8%), backache (58.8%), bony deformities (58.8%), joint pain (52.9%), fractures (29.4%) and dental abnormalities (23.5%). Radiological abnormalities noted were generalized bony deformities (58.8%), fractures (29.4%), and pseudo fractures (17.6%). Mesenchymal tumours were localized in the pelvis in one patient and in the right jaw in another. The patients were treated with calcium (elemental calcium 1 g/d) and oral phosphate supplements (dose 30 – 50mg/kg/day in divided doses) along with active vitamin D supplements (dose 1- 3 μg/day) and followed up for a mean of 2 yr. Two patients also received growth hormone (GH) therapy in the dose of 2U/day for 6 and 18 months respectively. Symptomatic well being was reported by all the patients and improvement was noted in the levels of phosphate (P<0.005) and alkaline phosphatase (P<0.05) after treatment. Interpretation & Conclusions: A diagnosis of HRO should be considered in all patients presenting with short stature, deformities or musculoskeletal pains along with low serum phosphate with normal iPTH and 25 – hydroxy vitamin D.

Hypophosphatemia: an evidence-based problem-solving approach to clinical cases

Hypophosphatemia is defined as a serum phosphate level of less than 2.5 mg/dL [0.8 mmol/L]. Hypophosphatemia is caused by inadequate intake, decreased intestinal absorption, excessive urinary excretion, or a shift of phosphate from the extracellular to the intracellular compartments. Renal phosphate wasting can result from genetic or acquired renal disorders. Acquired renal phosphate wasting syndromes can result from vitamin D deficiency hyperparathyroidism, oncogenic osteomalecia, and Fanconi syndrome. Genetic disorders of renal hypophosphatemic disorders generally manifest in infancy and are usually transmitted as an X-linked hypophosphatemic rickets. Symptoms of hypophosphatemia are nonspecific and most patients are asymptomatic. Severe hypophosphatemia may cause skeletal muscle weakness, myocardial dysfunction, rhabdomyolysis, and altered mental status. The diagnostic approach to hypophosphatemia should begin with the measurement of fractional phosphate excretion; if greater than 15% in the presence of hypophosphatemia, the diagnosis of renal phosphate wasting is confirmed. Renal phosphate wasting can be divided into 3 types based upon serum calcium levels: primary hyperparathyroidism [high serum calcium level], secondary hyperparathyroidism [low serum calcium level], and primary renal phosphate wasting [normal serum calcium level]. Phosphate supplementations are indicated in patients who are symptomatic or who have a renal tubular defect leading to chronic phosphate wasting. Oral phosphate supplements in combination with calcitriol are the mainstay of treatment. Parenteral phosphate supplementation is generally reserved for patient with life-threatening hypophosphatemia [serum phosphate < 2.0 mg/dL]. Intravenous phosphate [0.16 mmol/kg] is administered at a rate of 1 mmol/h to 3 mmol/h until a level of 2 mg/dL is reached

Tumor-induced osteomalacia: a case report / Osteomalácia induzida por tumor: relato de caso

Tumor-induced osteomalacia (TIO) is a rare paraneoplasic syndrome with overproduction of fibroblast growth factor 23 as a phosphaturic agent, leading to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of 1,25-dihydroxyvitamin D. Diagnosis of this disease is often challenging. The following case report described a middle-aged man with symptoms of bone pain and severe muscle weakness, who was found to have TIO. The tumor responsible for the symptoms was localized on his thigh and its resection resulted in normalization of blood chemistry and complaints. Subsequent microscopic examination revealed a phosphaturic mesenchymal tumor, mixed connective tissue type. The authors reinforce the importance of recognition of this disease, as severe disability and even death can be avoided with the surgical removal of the causative tumor.

Osteomalácia induzida por tumor (OIT) é uma síndrome paraneoplásica rara, causada por hiperprodução do agente fosfatúrico, levando a hipofosfatemia e hiperfosfatúria crônicas, associadas a níveis reduzidos ou inapropriadamente normais de 1,25-dihidroxivitamina D. O diagnóstico dessa doença é, geralmente, desafiador. O relato de caso aqui apresentado descreveu um homem de meia-idade, com quadro inicial de dor óssea, fraqueza muscular extrema e hipofosfatemia, com diagnóstico tardio de OIT. O tumor responsável pelos sintomas foi localizado em membro inferior, e sua exérese resultou em normalização das alterações bioquímicas e dos sintomas. O exame microscópico da lesão revelou tumor mesenquimal fosfatúrico, tecido conectivo misto. Os autores reforçam a importância do reconhecimento dessa entidade, uma vez que a remoção do tumor responsável pelos sintomas pode evitar sérias complicações ou mesmo a morte.

Correção da hipofosfatemia grave com dialisato enriquecido de fósforo em paciente hemodialisado / Treatment of serious hypophophatemia with phosphorus-enriched hemodialysis in patient in dialysis units

Introdução: A hipofosfatemia é definida como fósforo plasmático menor que 2,5 mg/dl podendo ser severa se inferior a 1,0 mg/dl. Ocorre em 2 a 5 pacientes hospitalizados, sendo descrita em pacientes com insuficiência renal crônica (IRC) submetidos a tratamento dialítico intenso. O quadro clínico decorre da diminuição de 2,3-difosfoglicerato e de outros compostos energéticos do metabolismo celular (ATP), podendo resultar em diminuição da contratilidade diafragmática, rabdomiólise, disfunção hematológica, miocárdica e da parte central do sistema nervoso. Metodologia: Este trabalho é um estudo retrospectivo realizado por meio de pesquisa do prontuário do paciente em programa regular de hemodiálise na Santa Casa de Misericórdia de Marília, no período de janeiro de 2003 a março de 2004, analisando-se os exames clínicos e laboratoriais apresentados pelo paciente, bem como o resultado das intervenções de suplementação efetuadas. Discussão: Num estudo retrospectivo de três anos em 149 pacientes sob hemodiálise com bicarbonato, baixos níveis de fosfato foram encontrados em 11 (7,3).

Distúrbio de cálcio e fósforo na infância / Calcium and phosphate disorders’s in childhood

Este artigo de revisão aborda aspectos gerais do metabolismo e da hemeostase do cálcio e do fósforo, bem como a fisiopatologia, as principais causas, as manifestações clínicas, os passos para o diagnóstico e o tratamento dos distúrbios do cálcio (hipocalcemia e hipercalcemia) e do fósforo ( hipofosfatemia e hiperfosfatemia) na infância e na adolscência.

Hiperparatireoidismo associado à osteomalacia hipofosfatêmica do adulto: relato de caso e revisão da literatura / Hyperparathyroidism associated with hypophosphatemic osteomalacia: case report and review of the literature

A osteomalacia hipofosfatêmica é uma doença rara caracterizada por hipofosfatemia, níveis elevados de fosfatase alcalina e diminuição da densidade óssea. O tratamento é realizado com suplementação oral com fosfato e vitamina D e, nos casos de osteomalacia oncogênica, com a ressecção do tumor. Relatamos o caso de uma paciente que apresentou quadro de osteomalácia hipofosfatêmica de causa indeterminada. Apesar de extensivamente procurado, nenhum tumor produtor de substância hipofosfatêmica foi localizado. A paciente foi tratada como suplementação de fosfato e vitamina D por longo período, evoluindo com quadro de hiperparatireoidismo terciário. A retirada de três paratireóides não normalizou os níveis de PTH e a paciente recusou-se a continuar a investigação e o tratamento. Após dez anos de tratamento irregular, foi internada por insuficiência respiratória causada por colabamento do arcabouço costal e múltiplas fraturas, evoluindo para o óbito. Os autores discutem a relação entre osteomalácia e hiperparatireoidismo e o curso agressivo da doença.

Síndrome de huesos hambrientos: experiencia clínica en su diagnóstico y tratamiento / Hungry bone syndrome: report of 4 cases

Hungry bone syndrome is a unusual complication of the postoperative period of primary hyperparathyroidism. This syndrome is characterized by hypocalcemia, hypophosphatemia and hypomagnesemia, due to an excessive bone remineralization. We report the clinical features, laboratory and therapy in four females (aged 39 to 73 years old) with a long standing hyperparathyroidism, elevated alkaline phosphatases and decreased bone mineralization in two. The mean size of the adenoma was 2.9 ñ 1.1 cm. Hypocalcemia appeared between days 1 and 6 of the postoperative period. All were treated with calcium, calcitriol and magnesium at different timing and dosages. The mean hospitalization period was 19.8 ñ 2.1 days. As reported previously, low bone mineralization and a large adenoma are risk factors for the syndrome. Serial monitoring of serum calcium and magnesium and an early supplementation of these minerals could prevent hypocalcemia and decrease the hospitalization time

Sídrome de Realimentación

Bajo el término de síndrome de realimentación se agrupan una serie de trastornos metabólicos como hipofosfatemia severa entre otros, observados en pacientes desnutridos sometidos a diferentes terapias de repleción nutricional, bien por vía parenteral o enteral. Se presentan dos casos con manifestaciones similares luego de iniciar la terapia de realimentación, uno parenteral y otro enteral, que mostraton cifras bajas de fósforo con trastornos de la conciencia y neuromusculares que cedieron con la suplementación de este anión. El propósito de la actual revisión es ampliar la definición del síndrome y clarificar los otros trastornos, además de la hipofosfatemia encontrados con la repleción nutricional, así como tipificar los diferentes pacientes en quienes es posible que aparezca esta complicación y por último hacer recomendaciones para su reconocimiento y más importante aún; para su prevención.

Hipocalcemia, hipomagnesemia e hipofosfatemia en pacientes pediátricos críticamente enfermos

Las alteraciones en las concentraciones séricas de iones como el calcio, el magnesio y el fósforo han sido estudiadas extensamente en los últimos años en pacientes críticamente enfermos y han sido asociadas con aumento de la mortalidad. En los reportes de Broner, de valores de electrolitos en pacientes pediátricos, al ingreso en una unidad de cuidado intensivo (1), la alteración electrolítica más frecuente fue alteración en la concentración de magnesio sérico (43.4 por ciento) de los pacientes, estando 25.6 por ciento de éstos por debajo y 17.8 por ciento por encima de los valores considerados como normales (0.74 - 0.95 mmol/dl) y encontrándose además una rata significativamente diferente de mortalidad (38 por ciento) en los pacientes hipermagnesémicos. Se encontró además 16.5 por ciento de alteración en los valores de calcio ionizado y una correlación estadísticamente significativa entre la presencia de hipocalcemia ionizada y mayor mortalidad. Los valores de calcio total no se correlacionaron con los valores de calcio iónico. Otro estudio realizado por Cárdenas-Rivero y cols (2), reporta una incidencia de hipocalcemia ionizada de 18 por ciento entre pacientes pediátricos que ingresan a una UCIP, correlacionando además la presencia de hipocalcemia ionizada con una mayor severidad de la enfermedad y una mayor mortalidad. El reporte de Reinhart y Desbiens (3) muestra una incidencia de 20 por ciento de hipomagnesemia y de 9 por ciento de hipermagnesemia en adultos que ingresan a una UCI médica. Se ha reportado una importante incidencia de hipofosfatemia en pacientes adultos que ingresan a unidades de cuidado intensivo por trauma como en el estudio de Daily (4), que sugiere la administración rutinaria de infusión de fosfato a estos pacientes para evitar la presencia de hipofosfatemia. Se conoce además la importancia de la fosfatemia como causante de muchas de las manifestaciones que presentan pacientes desnutridos a los que se les administra una dieta hipercalórica. Todos los anteriores datos nos llevan a revisar la fisiopatología de estas alteraciones, para poder detectar y tratar oportunamente sus manifestaciones.