Retraso diagnóstico y terapéutico en el hiperparatiroidismo primario. Un problema no resuelto / Diagnostic and treatment delay in primary hyperparathyroidism. A pending issue

INTRODUCCIÓN: El HPTP frecuentemente permanece sin diagnosticar en pacientes con hipercalcemia, lo que podría ocasionar un aumento de la morbilidad en estos sujetos. OBJETIVO: Identificar la presencia de hipercalcemia y de criterios de tratamiento quirúrgico (CTQ) no identificados desde al menos un año antes de su remisión a endocrinología en pacientes operados de HPTP. Valorar si este retraso terapéutico se asocia a mayor morbilidad. MÉTODOS: Estudio observacional en 116 pacientes consecutivos. Mediante la revisión de los registros anteriores a 12 meses previos a su derivación a endocrinología se dividieron en 4 grupos: hipercalcemia con CTQ (grupo 1, n = 43), hipercalcemia sin CTQ (grupo 2, n = 23), calcemias normales (grupo 3, n = 18) o ausencia de calcemias en dichos registros (grupo 4, n = 32). RESULTADOS: En 84 pacientes (72,4%) había calcemias previas, 66 (56,9%) con hipercalcemia, de ellos 43 (37%) con CTQ no valorados. La demora media hasta su remisión fue de 57 meses. Casi la mitad de las calcemias del grupo 1 procedían de urgencias. Respecto al grupo 4 los pacientes del grupo 1 tenían menor edad, mayor incidencia de nefrolitiasis e insuficiencia renal al remitírseles. Las calcemias en el momento de su derivación eran similares, superiores a las de los grupos 2 y 3. DISCUSIÓN: Los pacientes con HPTP y CTQ se remiten a endocrinología con un retraso medio de 5 años. La inadvertencia de la hipercalcemia y/o el desconocimiento de los CTQ retrasan esta derivación, determinada por hipercalcemias superiores, y se asocian a una afectación renal más severa. Son precisas medidas correctoras para evitar este retraso en el diagnóstico y curación del HPTP

INTRODUCTION: Primary hyperparathyroidism (PHPT) remains underdiagnosed among patients with hypercalcemia, potentially causing increased morbidity. OBJECTIVE: To identify in surgically operated patients the presence of overlooked hypercalcemia and patients with criteria for surgery (CFS) for PHPT at least one year prior to referral to Endocrinology, and to determine whether this diagnostic delay leads to increased morbidity. METHODS: An observational study was carried out in 116 consecutive patients. We evaluated electronic medical records registered at least 12 months prior to referral and divided them in four groups: hypercalcemia with CFS (group 1), hypercalcemia without CFS (group 2), normocalcemia (group 3), and cases without previous biochemical evaluation (group 4). RESULTS: A total of 84 patients (72.4%) had a previous measurement of serum calcium at a time interval of ≥ 12 months. Sixty-six (56.9%) had hypercalcemia and 43 of them (37%) had ≥ 1 CFS, with an average delay of 57 months in receiving proper evaluation. Almost half of the calcemia measurements in group 1 had been made in the emergency room. Patients from group 1 were younger, and had a greater frequency of nephrolithiasis and renal impairment than patients in group 4. The serum calcium values at referral were similar in both groups and higher than the values found in patients from the other two groups. DISCUSSION: In patients with PHPT and CFS, referral to an endocrinologist is made with an average delay of almost 5 years. The identified causes of this delay, which conditions more kidney disease, are unrecognized hypercalcemia and/or unawareness of the surgical criteria, while calcium elevations promote referral. Interventions are needed to avoid this delay in the diagnosis and resolution of PHPT

Hypercalcemic Disorders in Children.

Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.

Classification of Disorders of Bone and Calcium Metabolism.

Classification is a natural human trait that enables us to put what may otherwise be very complex subjects into some order. However, classification should be seen not as an end in itself but rather as a means to help us understand certain topics. In the case of medicine, classification helps to provide information about the causes underlying many of the conditions encountered and, in some cases, provides a rationale for developing new treatments. This chapter aims to provide a helpful (if complex) classification of diseases of bone and calcium and, where known, to describe the underlying genetic mechanisms.

Treatment of chronic hypercalcemia.

Hypercalcemia is a relatively frequent alteration, mostly associated to primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hypercalcemia. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy- associate hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The receptor activator of nuclear factor-κ ligand (RANKL) has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results .

[Cytokines in bone diseases. Cytokines and malignancy-associated hypercalcemia].

Malignancy-associated hypercalcemia is one of the commonest causes of hypercalcemia. Clinically, it has been subdivided into HHM (humoral hypercelcemia of malignancy) and LOH (local osteolytic hypercalcemia) . PTHrP (PTH related protein) , which has high homology with PTH in its N-terminus and binds to a common receptor (PTH1R) with PTH, plays a central role in the development of hypercalcemia in HHM. Although most features of HHM can be explained by excessive action of circulating PTHrP, decreased serum level of 1,25 (OH) (2)D and markedly suppressed bone formation found in HHM cannot be explained by the action of N-terminus of PTHrP. Fragments of PTHrP that do not bind to PTH1R, found in the circulation of HHM patients, or some other cytokines secreted by cancer cells may modify the clinical features of HHM. PTHrP also plays important roles in the development of LOH in some cancers, such as breast cancer. In this article, the role of cytokines, mainly PTHrP, in MAH will be reviewed.

Aspectos clínicos da hipocalcemia e da hipercalcemia

O cálcio é um íon divalente que participa de importantes funções no organismo. Entre elas pode-se citar: o metabolismo ósseo, a coagulação sanguínea, a adesão plaquetária, o potencial de ação das células neurológicas, a contração muscular e a sinalização celular como segundo mensageiro. Esta última função é fundamental para a realização dos diversos processos tanto fisiológicos quanto os patológicos. Nos processos fisiológicos, podem-se citar: a secreção dos diversos hormônios, a fertilização e a divisão celular. Nos processos patológicos, a morte celular e a apoptose são os principais exemplos

Aspectos clínicos da hipocalcemia e da hipercalcemia / Clinical aspects of hypocalcemia and hypercalcemia

O cálcio é um íon divalente que participa de importantes funções no organismo. Entre elas pode-se citar: o metabolismo ósseo, a coagulação sanguínea, a adesão plaquetária, o potencial de ação das células neurológicas, a contração muscular e a sinalização celular como segundo mensageiro. Esta última função é fundamental para a realização dos diversos processos tanto fisiológicos quanto os patológicos. Nos processos fisiológicos, podem-se citar: a secreção dos diversos hormônios, a fertilização e a divisão celular. Nos processos patológicos, a morte celular e a apoptose são os principais exemplos (AU)

Primary liver lymphoma with hypercalcemia: a case report.

Primary liver lymphoma is extremely rare. The diagnosis depends on the physician's suspicions and histological examination. We report the case of a man aged 38 years who suffered from abdominal discomfort and hypercalcemia. Sonography showed a huge, solid liver tumor, and magnetic resonance imaging showed the tumor had characteristics of hypointensity on T1-weighted and hyperintensity on T2-weighted imaging. Primary liver lymphoma was diagnosed by histological examination from biopsy. We report this rare type of liver tumor and review the clinical presentation and treatment of the disease.

[Usefulness of Pak's test in Stapleton's modification in diagnosis of hypercalciuria in children]. / Przydatnosc testu Paka w modyfikacji Stapletona w diagnostyce hiperkalciuri u dzieci.

UNLABELLED: Recognition of the type of hypercalciuria in children in Pak's test in Stapleton's modification was performed. 26 children with hypercalciuria was enrolled to the study. 15/26 had positive family history. In all Pak's test in Stapleton's modification was done, blond tests of renal function (urea, creatinine), calcium-phosphate balance (Ca, P, ALP, PTH, Vit D3 metabolites) and in 24 hr urine collection: promoters and inhibitors of crystallization, 24 hr urine pH measurement was performed. RESULTS: In 18 children--absorptive hipercalciuria: type II, in 1--type I, renal in 4; complex mechanism in 3, hypocitraturia was recognized in 4. Normalization of calciuria was obtained in 16 out of 26. In 3 others new formation of kidney stones was observed. CONCLUSIONS: Performation of Pak's test in Stapleton's modification allows to establish a type of hypercalciuria in children and recognize a pathomechanism of disease.

Idiopathic hypercalciuria in children. Classification, clinical manifestations and outcome.

Between 1981 and 1983, 49 children aged 2 to 15 years were diagnosed as having idiopathic hypercalciuria (IH). They were divided into 3 groups based on their response to dietary manipulation: group I (32/49) had absorptive hypercalciuria; group II (8/49) had renal hypercalciuria and group III (6/49) had sodium-dependent hypercalciuria. Response to diet was more reliable than Pak's test in differentiating between the three groups. A control group (CG) of 45 healthy, age matched children determined baseline levels for all metabolic parameters. At the time of presentation IH children did not differ from the CG in height or weight. Fifty percent of IH children had first degree relatives with urolithiasis. Yet, only 16% of the IH children had urolithiasis, the majority presenting with gross hematuria and urinary tract infections (UTI). With few exceptions the clinical symptoms resolved when urine calcium excretion was controlled. Severe calcium restriction in a few patients produced osteoporosis and delayed bone age although growth velocity was unaffected. Thiazide therapy in a few patients produced some metabolic derangements. The authors conclude that IH in childhood is a benign disease which may present with UTI or hematuria. They further propose a new classification method based on response to dietary manipulation.