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4.
BJS Open ; 8(3)2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38747104

RESUMO

BACKGROUND: Multicentre studies have previously reported on national outcomes of surgery for primary hyperparathyroidism, but not investigated whether management and outcome are uniform among countries. This study investigated whether there are differences among European countries in operative management and outcome of surgery for primary hyperparathyroidism. METHODS: Using data from Eurocrine®, a pan-European registry for endocrine surgeries, a retrospective observational cross-sectional multicentre study with 99 participating centres in 14 European countries was performed. Data on age, sex, calcium levels, operative strategy, conversion rate and rate of failed exploration were analysed for patients who underwent initial surgery for sporadic primary hyperparathyroidism. Primary outcome measures were intention to perform limited parathyroidectomy and the rate of hypercalcaemia at first follow-up. RESULTS: A total of 9548 patients were registered between 2015 and 2020. There were 7642 (80%, range 74.5-93.2%) females. There was intention to perform limited parathyroidectomy in 7320 of 9548 (76.7%) operations, ranging from 498 of 1007 (49.5%) to 40 of 41 (97.6%) among countries. Hypercalcaemia at first follow-up (median time to follow-up 15 days) was found in 416 of 9548 (4.4%) operations, ranging from 0 of 119 (0%) to 3 of 38 (7.9%) among countries. CONCLUSION: This study demonstrated large differences in the intention to perform limited parathyroidectomy for primary hyperparathyroidism among European countries, as well as differences in the rate of postoperative hypercalcaemia. Future studies are needed to evaluate the impact of these different healthcare practices on patient outcomes.


Assuntos
Hipercalcemia , Hiperparatireoidismo Primário , Paratireoidectomia , Humanos , Hiperparatireoidismo Primário/cirurgia , Feminino , Masculino , Paratireoidectomia/estatística & dados numéricos , Europa (Continente)/epidemiologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Estudos Transversais , Hipercalcemia/etiologia , Idoso , Adulto , Resultado do Tratamento , Sistema de Registros
5.
BMC Vet Res ; 20(1): 227, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38790012

RESUMO

BACKGROUND: Pamidronate is used for the treatment of hypercalcemia. However, a rare but potential adverse event of pamidronate treatment is hypocalcemia. This report describes an unusual case of severe, irreversible hypocalcemia after a single injection of pamidronate for the treatment of hypercalcemia due to glucocorticoid withdrawal in a dog. CASE PRESENTATION: An 11-year-old castrated male Maltese dog presented with anorexia, vomiting, and diarrhea (day 0). The patient had calcinosis cutis throughout the body, calcification of intraabdominal organs, mild azotemia, and severe hypercalcemia. The severe calcification was attributed to long-term glucocorticoid administration, which was discontinued 1 month before presentation. Fluid therapy, diuretics, calcitonin, and a single intravenous injection of pamidronate were used for the treatment of hypercalcemia. On day 14, normocalcemia was achieved, but renal failure occurred. On day 20, severe and irreversible hypocalcemia occurred, and on day 42, the patient was euthanized at the owner's request because of worsened hypocalcemia and renal failure. CONCLUSIONS: Although hypocalcemia is an extremely rare adverse event of bisphosphonate treatment, bisphosphonates like pamidronate can result in potentially life-threatening conditions according to the patient's underlying conditions. Therefore, the patient's condition should be closely monitored and any underlying conditions should be carefully evaluated before initiating the treatment for hypercalcemia using pamidronate.


Assuntos
Conservadores da Densidade Óssea , Doenças do Cão , Glucocorticoides , Hipercalcemia , Hipocalcemia , Pamidronato , Animais , Cães , Pamidronato/uso terapêutico , Hipocalcemia/veterinária , Hipocalcemia/induzido quimicamente , Masculino , Hipercalcemia/induzido quimicamente , Hipercalcemia/veterinária , Doenças do Cão/induzido quimicamente , Doenças do Cão/tratamento farmacológico , Glucocorticoides/uso terapêutico , Glucocorticoides/efeitos adversos , Glucocorticoides/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico
7.
Dermatol Online J ; 30(1)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38762865

RESUMO

Subcutaneous fat necrosis of the newborn is a self-limited disorder of the panniculus that arises in the first six weeks of life. Some differential diagnoses may be difficult such as bacterial cellulitis or erysipelas. The prognosis is usually favorable but there are serious complications for which the patient must be regularly monitored, especially hypercalcemia. We report a case of a full-term newborn with a liquidated area of subcutaneous fat necrosis. A surgical incision was performed because of the discomfort and the lack of regression. Hypercalcemia and nephrocalcinosis appeared afterward. A set of clinical, biological, and histological arguments allows the diagnosis of subcutaneous fat necrosis. Follow-up to early detection and to manage such complications is necessary.


Assuntos
Necrose Gordurosa , Hipercalcemia , Gordura Subcutânea , Humanos , Necrose Gordurosa/patologia , Recém-Nascido , Gordura Subcutânea/patologia , Hipercalcemia/etiologia , Masculino , Nefrocalcinose/etiologia , Diagnóstico Diferencial , Feminino
9.
Addict Sci Clin Pract ; 19(1): 34, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693547

RESUMO

BACKGROUND: Zoledronate, a bisphosphonate, is a potent first-line treatment for osteoporosis. It is also a preferred treatment for hypercalcemia especially when unresponsive to intravenous fluids. Bisphosphonates can cause acute phase reactions that mimic opioid withdrawal symptoms, which can confound provider decision-making. Our case highlights cognitive bias involving a patient with opioid use disorder who received zoledronate for hypercalcemia secondary to immobilization and significant bone infection. CASE PRESENTATION: A 41-year-old male is admitted with a past medical history of active intravenous opioid use complicated by group A streptococcal bacteremia with L5-S1 discitis and osteomyelitis, L2-L3 osteomyelitis, and left ankle abscess/septic arthritis status post left ankle washout. His pain was well-controlled by acute pain service with ketamine infusion (discontinued earlier), opioids, acetaminophen, buprenorphine-naloxone, cyclobenzaprine, gabapentin, and naproxen. Intravenous opioids were discontinued, slightly decreasing the opioid regimen. A day later, the patient reported tachycardia, diaphoresis, myalgias, and chills, which the primary team reconsulted acute pain service for opioid withdrawal. However, the patient received a zoledronate infusion for hypercalcemia, on the same day intravenous opioids were discontinued. He had no other medications known to cause withdrawal-like symptoms per chart review. Therefore, it was suspected that an acute phase reaction occurred, commonly seen within a few days of bisphosphonate use. CONCLUSION: Zoledronate, well known for causing acute phase reactions, was likely the cause of withdrawal-like symptoms. Acute phase reactions with bisphosphonates mostly occur in the first infusion, and the incidence decreases with subsequent infusions. Symptoms typically occur 24-72 h post-infusion, and last at most for 72 h. Cognitive bias led the primary team to be concerned with opioid withdrawal rather than investigating other causes for the patient's presentation. Therefore, providers should thoroughly investigate potential etiologies and rule them out accordingly to provide the best care. Health care providers should also be aware of the implicit biases that potentially impact the quality of care they provide to patients.


Assuntos
Reação de Fase Aguda , Transtornos Relacionados ao Uso de Opioides , Síndrome de Abstinência a Substâncias , Ácido Zoledrônico , Adulto , Humanos , Masculino , Reação de Fase Aguda/induzido quimicamente , Conservadores da Densidade Óssea/efeitos adversos , Diagnóstico Diferencial , Hipercalcemia/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Síndrome de Abstinência a Substâncias/diagnóstico , Ácido Zoledrônico/efeitos adversos
10.
Biomolecules ; 14(5)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38785958

RESUMO

The active vitamin D metabolites, 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), are produced by successive hydroxylation steps and play key roles in several cellular processes. However, alternative metabolic pathways exist, and among them, the 4-hydroxylation of 25D3 is a major one. This study aims to investigate the structure-activity relationships of 4-hydroxy derivatives of 1,25D3. Structural analysis indicates that 1,4α,25(OH)3D3 and 1,4ß,25(OH)3D3 maintain the anchoring hydrogen bonds of 1,25D3 and form additional interactions, stabilizing the active conformation of VDR. In addition, 1,4α,25D3 and 1,4ß,25D3 are as potent as 1,25D3 in regulating the expression of VDR target genes in rat intestinal epithelial cells and in the mouse kidney. Moreover, these two 4-hydroxy derivatives promote hypercalcemia in mice at a dose similar to that of the parent compound.


Assuntos
Receptores de Calcitriol , Animais , Camundongos , Relação Estrutura-Atividade , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/química , Receptores de Calcitriol/genética , Ratos , Calcitriol/análogos & derivados , Calcitriol/química , Calcitriol/metabolismo , Calcitriol/síntese química , Masculino , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Vitamina D/química , Hipercalcemia/metabolismo , Rim/metabolismo
11.
Praxis (Bern 1994) ; 113(4): 106-110, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38779795

RESUMO

INTRODUCTION: We present a case of a 58-year-old man with a history of laryngo-pharyngectomy including bilateral thyroidectomy due to hypopharyngeal cancer presenting with lethargy, acute kidney failure, and hypercalcemia. Milk alkali syndrome was diagnosed given the history of high-dose calcium / vitamin D supplementation after ruling out other causes of hypercalcemia. After initial treatment with normal saline, furosemide and denosumab, the patient developed severe symptomatic hypocalcemia as a rare adverse effect of denosumab.


Assuntos
Injúria Renal Aguda , Hipercalcemia , Letargia , Humanos , Hipercalcemia/etiologia , Hipercalcemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Letargia/etiologia , Diagnóstico Diferencial , Hipocalcemia/diagnóstico , Hipocalcemia/etiologia , Hipocalcemia/tratamento farmacológico , Denosumab/efeitos adversos , Denosumab/uso terapêutico
12.
Curr Opin Nephrol Hypertens ; 33(4): 433-440, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690798

RESUMO

PURPOSE OF REVIEW: Activation of the calcium-sensing receptor (CASR) in the parathyroid gland suppresses the release of parathyroid hormone (PTH). Furthermore, activation of the renal CASR directly increases the urinary excretion of calcium, by inhibiting transepithelial calcium transport in the nephron. Gain-of-function mutations in the CASR gene lead to autosomal dominant hypocalcemia 1 (ADH1), with inappropriately low PTH levels and hypocalcemia, indicative of excessive activation of the parathyroid CASR. However, hypercalciuria is not always observed. The reason why the manifestation of hypercalciuria is not uniform among ADH1 patients is not well understood. RECENT FINDINGS: Direct activation of the CASR in the kidney has been cumbersome to study, and an indirect measure to effectively estimate the degree of CASR activation following chronic hypercalcemia or genetic gain-of-function CASR activation has been lacking. Studies have shown that expression of the pore-blocking claudin-14 is strongly stimulated by the CASR in a dose-dependent manner. This stimulatory effect is abolished after renal Casr ablation in hypercalcemic mice, suggesting that claudin-14 abundance may gauge renal CASR activation. Using this marker has led to unexpected discoveries regarding renal CASR activation. SUMMARY: These new studies have informed on renal CASR activation thresholds and the downstream CASR-regulated calcium transport mechanisms.


Assuntos
Rim , Receptores de Detecção de Cálcio , Receptores de Detecção de Cálcio/metabolismo , Receptores de Detecção de Cálcio/genética , Humanos , Animais , Rim/metabolismo , Hipercalciúria/metabolismo , Hipercalciúria/genética , Cálcio/metabolismo , Hipercalcemia/metabolismo , Hipercalcemia/genética , Claudinas/metabolismo , Claudinas/genética , Hipocalcemia , Hipoparatireoidismo/congênito
13.
Intern Med J ; 54(6): 852-860, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38665051

RESUMO

Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation.


Assuntos
Cálcio , Homeostase , Transplante de Rim , Receptores de Detecção de Cálcio , Humanos , Receptores de Detecção de Cálcio/genética , Feminino , Cálcio/metabolismo , Hipocalcemia/genética , Hipocalcemia/etiologia , Hipercalciúria/genética , Hipercalcemia/genética , Rim/metabolismo , Mutação de Sentido Incorreto , Nefrocalcinose/genética , Falência Renal Crônica/cirurgia , Hipoparatireoidismo/congênito
14.
Medicina (B Aires) ; 84(2): 342-346, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38683521

RESUMO

Primary hyperparathyroidism (PHPT) is characterized by elevated levels of calcium and parathyroid hormone (PTH). However, the interpretation of diagnostic tests, such as serum calcium and PTH levels, is complex in pregnant women. The aim of this report is to present a case of PHTP in a pregnant adolescent, with a special emphasis on an uncommon complication, as well as diagnostic and treatment strategies. A 17-year-old pregnant female presented with hyperemesis gravidarum and neurological symptoms, leading to the diagnosis of cerebral venous thrombosis. Further investigations revealed hypercalcemia and persistently elevated PTH levels, consistent with PHPT. After localization studies, the patient underwent an emergency parathyroidectomy with a diagnosis of parathyroid adenoma. During follow-up, intrauterine growth restriction and severe preeclampsia developed, necessitating an emergency cesarean section. Both the mother and neonate had favorable outcomes. PHPT is an infrequent condition in the pregnant population, and its diagnosis can be challenging due to the overlap of symptoms with normal physiological changes during pregnancy. The occurrence of uncommon complications, such as thrombotic phenomena, highlights the need for a comprehensive approach to ensure early detection and management. In most cases, parathyroidectomy is the treatment of choice.


El hiperparatiroidismo primario (HPTP) se caracteriza por niveles elevados de calcio y hormona paratiroidea (PTH). Sin embargo, la interpretación de pruebas diagnósticas, como los niveles de calcio sérico y PTH, es compleja en mujeres embarazadas. El objetivo de este reporte es presentar un caso de HPTP en una adolescente embarazada, con especial hincapié en una complicación infrecuente, así como en las estrategias diagnósticas y de tratamiento. Una mujer embarazada de 17 años presentó hiperémesis gravídica y síntomas neurológicos, lo que llevó al diagnóstico de trombosis venosa cerebral. Posteriores investigaciones revelaron hipercalcemia y niveles persistentemente elevados de PTH, consistentes con HPTP. Tras la realización de estudios de localización, la paciente fue sometida a una paratiroidectomía de emergencia con diagnóstico de adenoma de paratiroides. Durante el seguimiento, se desarrolló restricción del crecimiento intrauterino y preeclampsia grave, lo que resultó en la necesidad de realizar una cesárea de emergencia. Tanto la madre como el neonato evolucionaron favorablemente. El HPTP es una condición infrecuente en la población embarazada y su diagnóstico puede ser desafiante por la superposición de síntomas con los cambios fisiológicos normales del embarazo. La aparición de complicaciones infrecuentes, como fenómenos trombóticos, resalta la necesidad de un abordaje integral para garantizar la detección y el manejo temprano. En la mayoría de los casos, la paratiroidectomía es el tratamiento de elección.


Assuntos
Hiperparatireoidismo Primário , Neoplasias das Paratireoides , Paratireoidectomia , Humanos , Feminino , Gravidez , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/sangue , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/cirurgia , Neoplasias das Paratireoides/diagnóstico , Adolescente , Adenoma/complicações , Adenoma/cirurgia , Adenoma/diagnóstico , Hormônio Paratireóideo/sangue , Complicações Neoplásicas na Gravidez/cirurgia , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações na Gravidez/diagnóstico , Hiperêmese Gravídica/complicações , Hiperêmese Gravídica/diagnóstico , Hipercalcemia/etiologia , Hipercalcemia/sangue , Hipercalcemia/diagnóstico , Cesárea
15.
Front Endocrinol (Lausanne) ; 15: 1355916, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665259

RESUMO

Introduction: 24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH)2D3. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild. Aim of the study: We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases. Case presentation: We report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)2D3 concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC-MS/MS, which revealed high levels of 25(OH)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25(OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively). Conclusions: The diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC-MS/MS may help to identify carriers of CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment.


Assuntos
Adenoma , Hipercalcemia , Neoplasias das Paratireoides , Vitamina D3 24-Hidroxilase , Humanos , Hipercalcemia/genética , Feminino , Pessoa de Meia-Idade , Vitamina D3 24-Hidroxilase/genética , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/cirurgia , Neoplasias das Paratireoides/patologia , Adenoma/genética , Adenoma/complicações , Adenoma/patologia , Mutação , Paratireoidectomia
17.
Eur J Obstet Gynecol Reprod Biol ; 297: 270-274, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38604920

RESUMO

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive ovarian malignant neoplasm lacking a unified clinical management process. Most patients are diagnosed at an advanced stage and have an extremely poor prognosis with an overall probability of survival less than 10 %. Here, we describe the case of a patient with advanced SCCOHT achieved a survival of over 5 years after receiving multiple cycles of immunotherapy combined with anti-angiogenic therapy or CDK4/6 inhibitors. At the same time, we also summarized the case reports and clinical trials of immunotherapy in SCCOHT.


Assuntos
Carcinoma de Células Pequenas , Hipercalcemia , Imunoterapia , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/tratamento farmacológico , Carcinoma de Células Pequenas/terapia , Carcinoma de Células Pequenas/tratamento farmacológico , Hipercalcemia/terapia , Hipercalcemia/etiologia , Imunoterapia/métodos , Pessoa de Meia-Idade , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
18.
BMC Pulm Med ; 24(1): 204, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658913

RESUMO

BACKGROUND: The prevalence of non-HIV related Pneumocystis jirovecii pneumonia (PJP) is increasing with use of immunosuppressive therapies. There are case reports of solid organ transplant recipients on immunosuppressive therapy presenting with mild hypercalcemia, leading to a diagnosis of PJP. Recent studies have shown efficacy of PJP prophylaxis for patients treated with rituximab with a favourable adverse effect profile. CASE PRESENTATION: A 78-year-old male with a history of PR3-ANCA vasculitis, chronic kidney disease and heart failure with reduced ejection fraction presented to our tertiary care hospital with a two-week history of confusion and non-productive cough. Background immunosuppression with rituximab was completed every six months. The patient was found to have hypercalcemia and new infiltrates and ground glass opacities on cross-sectional imaging. Bronchoscopy was performed that was positive for Pneumocystis jirovecii. He was treated with 21 days of trimethoprim-sulfamethoxazole and prednisone with resolution of symptoms and hypercalcemia. CONCLUSIONS: Herein, we present a novel case of PJP in a non-transplant recipient preceded by hypercalcemia. Our case demonstrates the importance for a high suspicion for PJP in chronically immunosuppressed patients on rituximab presenting with PTH-independent hypercalcemia.


Assuntos
Hipercalcemia , Hospedeiro Imunocomprometido , Pneumocystis carinii , Pneumonia por Pneumocystis , Rituximab , Combinação Trimetoprima e Sulfametoxazol , Humanos , Masculino , Idoso , Pneumocystis carinii/isolamento & purificação , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/complicações , Pneumonia por Pneumocystis/tratamento farmacológico , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Prednisona/uso terapêutico , Broncoscopia
19.
Eur J Endocrinol ; 190(4): 296-306, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38561929

RESUMO

OBJECTIVE: The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants. DESIGN AND METHODS: To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs. RESULTS: Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT. CONCLUSIONS: This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.


Assuntos
Hipercalcemia , Hipocalcemia , Adolescente , Humanos , Cálcio , Células HEK293 , Hipercalcemia/genética , Hipocalcemia/genética , Mutação/genética , Receptores de Detecção de Cálcio/genética
20.
Cancer Rep (Hoboken) ; 7(4): e2047, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38577726

RESUMO

BACKGROUND: Parathyroid carcinoma (PC) is a rare endocrine malignancy causing pathological changes such as abnormal bone metabolism, elevated serum calcium, and impaired renal function, and uncontrollable hypercalcemia is the main cause of death in PC patients. The diagnosis of PC is challenging and relying on postoperative histopathology. Radical surgery at the first time is the only effective therapy to cure PC. Hungry bone syndrome (HBS) is a relatively uncommon complication of parathyroidectomy characterized by profound and prolonged hypocalcemia, timely electrolyte monitoring and alternative interventional protocols can prevent symptomatic hypocalcemia. CASE: A 57-year-old man presented with multiple pathological fractures and muscle atrophy as the main symptoms accompanied by bone pain, hypercalcemia, elevated parathyroid hormone (PTH), and an enlarged left-sided neck mass. After consultation of multidisciplinary team, he was treated conservatively with plaster bandage fixation and infusion of intravenous zoledronic acid; and then complete resection of parathyroid mass + removal of involved tissue structures + left thyroid and isthmus lobectomy + lymph node dissection in the VI region in left neck were performed. The postoperative histopathology suggested a diagnosis of parathyroid carcinoma. Calcium and fluid supplementation and oral levothyroxine tablets were given postoperatively. Unexpectedly, the patient's PTH level decreased rapidly at 24 h postoperative, and serum calcium and phosphorus decreased continuously, and he felt numb around perioral sites and fingertips, which considered to be postoperative HBS complicated by parathyroidectomy. Then, a large amount of calcium supplementation and vitamin D were given timely and the patient got better at 1 month postoperatively. At 9-month postoperative, his bone pain and fatigue were significantly relieved compared with before with calcium, phosphorus, and PTH levels at normal range. CONCLUSION: The possibility of parathyroid disease, particularly PC, should be considered in the presence of multiple pathological fractures, muscle atrophy, generalized bone pain, hypercalcemia, and clear neck mass. Radical resection of the tumor lesions at the first surgery is a key element affecting the prognosis of PC, and the effective management of preoperative hypercalcemia and postoperative HBS is also of great significance for improving prognosis.


Assuntos
Fraturas Espontâneas , Hipercalcemia , Hipocalcemia , Neoplasias das Paratireoides , Masculino , Humanos , Pessoa de Meia-Idade , Hipocalcemia/etiologia , Hipocalcemia/complicações , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/cirurgia , Cálcio , Hipercalcemia/complicações , Fraturas Espontâneas/complicações , Fósforo , Atrofia Muscular/complicações , Dor
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