Hypercalcemia and renal function impairment associated with vitamin D toxicity: case report / Hipercalcemia e prejuízo de função renal associados à intoxicação por vitamina D: relato de caso

Abstract Nowadays vitamin D (25-OHD) deficiency is supposed to be a global epidemic condition. Expectedly, vitamin D measurement and intake exponentially increased in Brazil in this decade. Although the benefit of vitamin D to general health is still in debate, its indiscriminate use potentially may lead to enhance the incidence of vitamin D intoxication, which is considered a rare disorder. We report a case of a 70 year old diabetic male with chronic renal disease (blood creatinine of 1.6 mg/dL) who progressed suddenly to acute kidney injury (blood creatinine of 5.7 mg/dL) associated with hypercalcemia and high blood levels of vitamin D. Vitamin D and calcitriol were discontinued and hypercalcemia was managed by hydration followed by furosemide. Thereafter, disodium pamidronate was administered and the patient did not undergo on dialysis. It took approximately 14 months to normalize 25-OHD levels and blood creatinine returned to basal levels only after 24 months. The indicated labeling dosage was 2000 IU, but most likely the vitamin D manipulated preparation was higher as the vitamin D blood levels were very high. Although rare, vitamin D intoxication is becoming more frequent as the patients use frequently manipulated preparations that could be subject to errors in the manufacturing and labeling of the tablets or capsules. The present report alerts to the potential increase in the incidence of severe vitamin D intoxication due to the frequent use of this secosteroid as a nutritional supplement. At the same time, it is necessary to improve regulation on the nutrient supplement market.

Resumo Atualmente, muitos brasileiros têm utilizado vitamina D (25-OHD) como suplemento vitamínico para prevenção de diversas doenças crônicas, apesar da falta de dados científicos consistentes sobre o papel deste secosteroide na prevenção de doenças que não as do metabolismo mineral. A intoxicação por vitamina D é rara, mas devido ao seu uso indiscriminado tem ocorrido com maior frequência. Nesse relato, um homem diabético de 70 anos de idade com doença renal crônica (creatinina sérica de 1,6 mg/dL) passou a fazer uso de colecalciferol e calcitriol para recomposição dos níveis de 25-OHD, que eram de 16 ng/mL. O mesmo desenvolveu quadro de lesão renal aguda (creatinina = 5,7 mg/dL), após 45 dias. Este processo emergiu em paralelo ao surgimento de hipercalcemia e níveis circulantes elevados de vitamina D. Foram suspensas a administração de vitamina D e calcitriol, a hipercalcemia foi tratada com hidratação endovenosa, seguida de diurético de alça e posteriormente pamidronato. O paciente, que havia sido encaminhado para diálise, não necessitou desse tratamento. Os níveis de 25-OHD voltaram ao normal 14 meses após a sua suspensão, e os níveis de creatinina voltaram aos patamares anteriores 24 meses após esse evento. A dose prescrita de vitamina D correspondeu a 2000 UI/dia, a qual não é considerada inadequada segundo recomendações atuais. Existe, no entanto, na literatura controvérsia quanto à sensibilidade individual à vitamina D. Não pode ser descartado o uso inapropriado pelo paciente e nem eventual erro de manipulação. Embora raro, o quadro de intoxicação por vitamina D é grave e potencialmente pode levar a complicações clínicas irreversíveis.

Hipercalcemia tumoral: a propósito de tres casos: [revisión] / Tumor related hypercalcemia: a review of three cases: [review]

Hypercalcemia is an infrecuent complication in pediatric oncology, with an incidence between 0,5 and 3 percent. It can occur at diagnosis, during the disease course or at relapse, and it is resolved by treating the underlying pathology, requiring in some cases the use of specific therapy such as calcitonin and biphosphonates. This article presents 3 cases of children with cancer and hypercalcemia during their illness, analyzing its clinical presentation, pathophysiology and treatment.

La hipercalcemia es una complicación infrecuente en niños con cáncer, con una incidencia que oscila entre 0,5 y 3 por ciento. Se puede presentar al diagnóstico, durante el tratamiento o en la recaída de una neoplasia, se resuelve al tratar la enfermedad de base, pudiendo además, requerir el uso de terapia específica como calcitonina y bifosfonatos. En el presente artículo se revisan 3 casos clínicos de niños con cáncer que presentaron hipercalcemia en algún momento de su enfermedad, se discute su forma de presentación, fisiopatología y manejo.

Disorders of calcium, phosphorus and magnesium metabolism.

Abnormalities of calcium, magnesium and phosphorus are common in hospitalized patients. Infrequently patients might present in the outpatient settings with non-specific symptoms that might be due to abnormalities of divalent cation (magnesium, calcium) or phosphorous metabolism. Several inherited disorders have been identified that result in renal or intestinal wasting of these elements. Physicians need to have a thorough understanding of the mechanism of calcium, magnesium and phosphorous metabolism and diagnoses disorders due to excess or deficiency of these elements. Prompt identification and treatment of the underlying disorders result in prevention of serious morbidity and mortality.

Role of calcium-sensing receptor in bone biology.

Bone turnover helps accomplish long-term correction of the extracellular calcium (Ca2+ o) homeostasis by the actions of osteoblasts and osteoclasts. These processes are highly regulated by the actions of hormones, most prominently parathyroid hormone (PTH), the release of which is a function of the Ca2+ o, and is regulated by the action of the Ca2+ -sensing receptor (CaR) in the parathyroid gland. Various mutations of the CaR gene give rise to gain or loss of functions leading respectively to hypo- or hypercalcaemic conditions. CaR could conceivably be a target for local changes in the Ca2+ o in the bone microenvironment thereby acting as a 'growth factor' in various cells residing in the bone marrow. This review discusses about the roles of the CaR in bone. In osteoblasts, CaR promotes its proliferation, differentiation and mineralization. In osteoclasts, CaR mediates high Ca2+ o-stimulated osteoclast differentiation as well as osteoclast apoptosis. CaR regulates localization of haematopoietic stem cells from the foetal liver to endosteal niche, the socalled homing. Although the CaR plays a key role in the defense against hypercalcaemia, its function can be aberrant in humoral hypercalcaemia of malignancy in which CaR activation stimulates secretion of parathyroid hormone-related peptide (PTHrP) secretion. Increased levels of PTHrP cause a vicious hypercalcaemic state resulting from its increased bone-resorptive and positive renal calcium reabsorbing effects give rise to hypercalcaemia. CaR mediates a variety of functions of Ca2+ o in the bone microenvironment under both normal and pathological conditions.

Extracellular calcium-sensing receptor: structural and functional features and association with diseases

The recently cloned extracellular calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. This receptor is expressed in all tissues related to this control (parathyroid glands, thyroid C-cells, kidneys, intestine and bones) and also in tissues with apparently no role in the maintenance of extracellular calcium levels, such as brain, skin and pancreas. The CaR amino acid sequence is compatible with three major domains: a long and hydrophilic aminoterminal extracellular domain, where most of the activating and inactivating mutations described to date are located and where the dimerization process occurs, and the agonist-binding site is located, a hydrophobic transmembrane domain involved in the signal transduction mechanism from the extracellular domain to its respective G protein, and a carboxyterminal intracellular tail, with a well-established role for cell surface CaR expression and for signal transduction. CaR cloning was immediately followed by the association of genetic human diseases with inactivating and activating CaR mutations: familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism are caused by CaR-inactivating mutations, whereas autosomal dominant hypoparathyroidism is secondary to CaR-activating mutations. Finally, we will comment on the development of drugs that modulate CaR function by either activating (calcimimetic drugs) or antagonizing it (calcilytic drugs), and on their potential therapeutic implications, such as medical control of specific cases of primary and uremic hyperparathyroidism with calcimimetic drugs and a potential treatment for osteoporosis with a calcilytic drug

Características clínicas y evolución de la hipercalcemia grave por hiperparatiroidismo primario en pacientes intervenidos quirúrgicamente / Clinical characteristics and outcome of surgically treated severe hypercalcemia: due to primary hyperparathyroidism

Objetivo. Describir la forma de presentación, diagnóstico, tratamiento y evolución de la hipercalcemia grave asociada a hiperparatiroidismo primario (HPTP) en una serie de pacientes. Material y métodos. Se evaluaron las características clínicas, forma de presentación, hallazgos quirúrgicos, tratamiento, evolución y complicaciones de 21 pacientes con HPT cuyo calcio sérico fue igual o superior a 14 mg/dL. El grupo fue tomado de un total de 118 enfermos intervenidos quirúrgicamente por HPTP en el periodo de estudio. Resultados. La edad promedio fue de 47 ñ 17 años y la relación M:F de 4:17. El 95 por ciento de los pacientes tuvo uno o más síntomas, el 62 por ciento mostró alteraciones en el electrocardiograma y el 76 por ciento mostró alteraciones radiológicas. Todos los pacientes recibieron hidratación intensa durante el preoperatorio, con frecuencia asociada a la administración de diuréticos. Se estableció el diagnóstico de enfermedad uniglandular (adenoma) en 13, enfermedad multiglandular (hiperplasia) en 4 y carcinoma en 4. En todos los pacientes con enfermedad benigna se logró la normalización de las cifras de calcio. Conclusiones. La hipercalcemia grave es una entidad relativamente frecuente en la población de enfermos con HPTP en nuestro hospital. La mayor parte de pacientes presentó manifestaciones clínicas o paraclínicas atribuibles a la enfermedad. Los resultados del tratamiento quirúrgico son satisfactorios en pacientes con enfermedad benigna.

Abordagem clínico-laboratorial no diagnóstico diferencial de hipercalcemia / Clinical and laboratorial approach in differential diagnosis of hypercalcemia

A hipercalcemia é anormalidade metabólica comum, porém pouco diagnosticada por ser frequentemente assintomática. Aproximadamente 90 por cento dos casos são decorrentes de hiperparatireoidismo primário (HPT) ou doença maligna complicada por hipercalcemia, estando prevalentes em pacientes ambulatoriais e hospitalizados, respectivamente. Laboratoriamente, o HPT e hipercalcemia humoral maligna apresentam algumas semelhanças, tais como: aumento do AMPc nefrogênico, hipofosfatemia e hipercalciúria. Porém, o quadro clínico da hipercalcemia associada à malignidade é mais severo e, geralmente, o paciente apresenta-se clinicamente debilitado pela doença, com muitas metástases. A dosagem sérica de PTH intacto (PTHi) é fundamental para o diagnóstico definitivo, estando o PTHi elevado ou normal no HPT primário, e suprimido na malignidade. Os mecanismos de hipercalcemia da doença maligna são: secreção de fatores humorais que alteram a homeostase do cálcio e fatores locais produzidos pelos tumores metastásicos ou hematológicos no osso, causando aumento da reabsorção osteoclástica. A proteína relacionada ao hormônio da paratireóide (PTHrP) tem sido implicada na maioria dos casos de hipercalcemia devido a tumores sólidos. Outros fatores como interleucina-6, fator de crescimento tumoral, fator de necrose tumoral e interleucina-1 podem modular os efeitos do PTHrP nos órgãos-alvo, e em alguns tumores, ativam diretamente o osteoclastos como por exemplo no mieloma múltiplo. A hipercalcemia pode estar menos freqüentemente associada a algumas doenças endócrinas como tireotoxicose, feocromocitoma, doença de Addison e neoplasia endócrina múltipla tipos I e IIA. Algumas drogas podem causar esse distúrbio metabólico, merecendo destaque a vitamina D, os diuréticos tiazídicos e o lítio. A sarcoidose é exemplo de doença granulomatosa que pode associar-se à hipercalcemia em 10 por cento dos casos e hipercalciúria em 50 por cento. O diagnóstico diferencial dos hipercalcemias é essencial para que haja uma abordagem terapêutica eficaz dessa anormalidade metabólica.

Experiencia en el uso del clodronato en tastasis oseas del cancer de la mama / Experience in using clodronato in breast cancer`s osseus methastasis

Los bifosfonatos son compuestos de estructura similar a los pirofosfatos, con un atomo de C uniendo los fosfatos. Son efectivos en el tratamiento de metastasis oseas por via oral o endovenosa, si bien no presentan accion antitumoral. Se presenta la evolucion de 5 pacientes que recibieron clodronato por via oral. En todas ellas se obtuvo mejoria del dolor oseo, con una mayor y mejor sobrevida, sin aparicion de fracturas, compresiones ni otras manifestaciones de recurrencia que necesitaran radio o quimioterapia. Dos casos llevan mas de dos años de tratamiento. El efecto del clodronato es mas favorable cuando se administra tempranamente, con la aparición de las metástasis óseas

Leiomiosarcoma duodenal e hipercalcemia / Duodenal leiomyosarcoma and hypercalcemia

La hipercalcemia es un trastorno metabólico frecuente en los pacientes con cáncer. Se asocia comúnmente con neoplasias mamarias, pulmonares y hematológicas. La relación entre hipercalcemia y leiomiosarcoma gastrointestinal es anecdótica. Se presenta el caso de un varón joven con leoimiosarcoma duodenal metastásico a hígado quien desarrolló hipercaldemia maligna refractaria a terapia convencional que mostró buena respuesta a quimioembolización y al nitrato de galio

An update on the discovery, pathophysiological actions, clinical manifestations and possible physiology of parathyroid related peptide

PTHrP has had an unidentified role in medicine since 1930, when Albright described a patient with renal cortical cell carcinoma with hypercalcemia. Since then hypercalcemia has been recognized as the most common paraneoplastic syndrome. At that time the concept of ®ectopic PTH syndrome® was introduced, and remained in literature until the true etiology was finally described. In the early 1970's Roof and Benson presented evidence that PTH in humoral hypercalcemia differed from ®authentic® PTH. This marked the starting point for researchers to try identifying the molecule that mimicked PTH action and structure. This molecule, named parathyroid-related peptide, has been associated to hypercalcemia seen with solid tumors, such as squamous cell carcinoma of the lung and renal cortical cell carcinoma. PTHrP has been demonstrated to have similar actions to PTH but to differ in decreasing osteoblastic activity while increasing osteoclastic activity. The more fascinating finding was the presence of the PTHrP genes throughout the body, mostly the lactating breast as well as the heart, lungs and skin among others. Despite its identification, finding its physiological roles on normal tissue still remains to be clarified

Un caso atípico de abdomen agudo / Atipical case of acute abdomen

Introducción: El potasio es el ión más importante en el funcionamiento de las células excitables, la hiperkalemia se relaciona con efectos peligrosos sobre miocardio, músculo liso y nervios periféricos. A pesar de la clara asociación fisiopatológica entre el aumento del potasio y el íleo paralítico, no se han hallado casos que mencionen al abdomen agudo como forma de presentación en la búsqueda bibliográfica por Medline de los últimos diez años. Se presenta por tanto un caso en el cual el motivo de consulta fue dolor abdominal. Presentación: Paciente de sexo femenino, 83 años, consulta por dolor abdominal muy intenso asociado a náuseas y oliguria de 24 hs de evolución. Antecedentes: tromboembolismo de pulmón a repetición a pesar de estar anticoagulada de forma suficiente, hipertensión pulmonar, fibrilación auricular, medicada con furosemida, espironolactoma, digoxina, acenocumarol. Examen físico: desasosegada, taquipneica, soplo de regurgitación tricúspidea, abdomen doloroso, sin ruidos hidroaéreos. Urea: 108 mg por ciento, creatinina: 1,91 mg/dl, K: 6,8 meq, Ph: 7,52, Po2: 142, PCo2 35, COH3 29,9. ECG: ritmo nodal. Colon por enema: dolicocolon. Ecografía abdominal y endoscopía esófago-gástrica normales. Se trata con soluciones polarizantes, cediendo el dolor abdominal y retornando el ritmo cardíaco a fibrilación auricular, recupera el ritmo diurético y normaliza urea y creatinina. Conclusiones: 1) Esta hiperkalemia sin fallo renal crónico previo fue multifactorial. a- Uso prolongado de espironolactona en paciente deshidratada con escaso aporte de Na. b- Seudohipoaldosteronismo. c- Alcalosis mixta. 2) Debido a la acción del potasio sobre las células excitables, la hiperkalemia puede provocar íleo paralítico y presentarse como abdomen agudo sobre todo en pacientes polimedicados

Hipercalcemia de la malignidad / Malignancy hypercalcemia

La hipercalcemia de la malignidad constituye la emergencia metabólica más frecuente en el área oncológica, pudiendo afectar hasta un 10-20 por ciento de los pacientes. La hipercalcemia afecta profundamente la calidad de vida del paciente con cáncer y compromete multiples sistemas orgánicos provocando alteraciones potencialmente letales a nivel neuromuscular, gastrointestinal, renal y cardiovascular. En la presente revisión se enfocan aspectois epidemiológicos, se analizan los mecanismos de producción de hipercalcemia en las diferentes neoplasias, se discuten las dificultades en el diagnóstico preciso de esta entidad y las causas desencadenantes del mismo y finalmente se plantean los diferentes tratamientos actuales así como los temas de controversia e investigación en el cuidado de los pacientes con cáncer.

Clodronate in hypercalcemia and osteolytic bone disease due to breast cancer

Progressive osteolysis is a significant cause for morbidity in patients with neoplasia affecting the skeleton. It gives rise to fractures, bone pain and hypercalcaemia. The mechanism for osteolysis is principally mediated by the activation of bone resorbing cells. The bisphosphonates are specific inhibitors of osteoclast mediated bone resorption and have been widely used in the management of osteolysis. Clodronate is one of the bisphosphonates that may be given by mouth or by parenteral injections. Both formulations lower serum calcium in the vast majority of affected patients due to the inhibition of bone resorption. Moreover, the agent also has significant effects on bone pain. There is increasing evidence that the long-term use of Clodronate decreases the incidence of intercurrent hypercalcaemia, bone pain and fracture and thereby improves the quality of life of affected patients