ABSTRACT
Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. PURPOSE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. CONCLUSION: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.
ABSTRACT
BACKGROUND: While clinical features of KCNJ5-mutated aldosterone-producing adenoma (APA) have been reported, evidence of its clinical outcomes is lacking. We aimed to synthesize available literature about the associations between KCNJ5 mutation with cardiovascular and metabolic outcomes among patients with APA. METHODS: In this systematic review of observational studies, MEDLINE and Embase were searched through August 2022. Two independent authors screened the search results and extracted data from eligible observational studies investigating cardiovascular or metabolic outcomes between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs. Risk of Bias In Non-randomized Studies of Interventions was used to assess the quality of the included studies. RESULTS: A total of 573 titles/abstracts were screened and after the expert opinion of the literature, full text was read in 20 titles/abstracts, of which 12 studies were included. Across 3 studies comparing the baseline or change in the cardiac function between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs, all studies reported the association between impaired cardiac functions and KCNJ5 mutation status. Among 6 studies evaluating the cure of hypertension after surgery, all studies showed that KCNJ5 mutation was significantly associated with the cure of hypertension. In quality assessment, 7 studies were at serious risk of bias, while the remaining studies were at moderate risk of bias. CONCLUSIONS: This systematic review provided evidence of the significant association between KCNJ5 mutation and unfavorable cardiovascular outcomes in patients with primary aldosteronism. Further research is needed to improve the quality of evidence on this topic and elucidate the underlying mechanisms of the potential burden of KCNJ5 mutation.
Subject(s)
Aldosterone , G Protein-Coupled Inwardly-Rectifying Potassium Channels , Mutation , Humans , G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics , Aldosterone/metabolism , Aldosterone/biosynthesis , Cardiovascular Diseases/genetics , Adrenal Cortex Neoplasms/genetics , Hyperaldosteronism/genetics , Adrenocortical Adenoma/genetics , Adrenocortical Adenoma/metabolism , Adenoma/genetics , Adenoma/metabolismABSTRACT
We investigated the impact of the Coronavirus disease 2019 (COVID-19) pandemic on the management of endocrine and metabolic disorders in Japan. We conducted a cross-sectional nationwide questionnaire survey targeting board-certified endocrinologists under the auspices of the Japan Endocrine Society. The questionnaire consisted of multiple-choice questions and open-ended responses. Out of approximately 2,700 specialists, 528 (19.5%) opted to participate, suggesting a high level of interest in COVID-19 management among endocrinologists. The study found that almost half of participants had encountered cases of endocrine and metabolic disorders following COVID-19 infection or vaccination. Conditions related to thyroid diseases, glucose metabolism disorders/diabetes, and hypothalamic-pituitary disorders were particularly prevalent. Diabetes and obesity were identified as having high rates of severe cases or fatalities due to COVID-19. The study also highlighted challenges in routine diagnosis and treatment, emphasizing the potential benefits of combining remote consultations with in-person visits to optimize the frequency of examinations and check-ups during infectious disease outbreak which disrupts access to healthcare providers. The insights obtained from this survey are expected to contribute to ensuring appropriate healthcare provision for patients with endocrine and metabolic disorders by using flexible consultation formats, particularly even in the conditions where medical access may be limited due to future outbreaks of emerging or re-emerging infectious diseases.
Subject(s)
COVID-19 , Endocrine System Diseases , Metabolic Diseases , SARS-CoV-2 , Humans , COVID-19/epidemiology , Japan/epidemiology , Cross-Sectional Studies , Metabolic Diseases/epidemiology , Endocrine System Diseases/epidemiology , Endocrine System Diseases/therapy , Surveys and Questionnaires , Female , Male , Societies, Medical , Endocrinologists , Adult , Middle Aged , Endocrinology/organization & administration , Practice Patterns, Physicians'/statistics & numerical dataABSTRACT
Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.
Subject(s)
Bexarotene , Dyslipidemias , Hypothyroidism , Humans , Bexarotene/adverse effects , Hypothyroidism/chemically induced , Hypothyroidism/epidemiology , Male , Female , Middle Aged , Retrospective Studies , Aged , Dyslipidemias/chemically induced , Japan/epidemiology , Thyroxine/blood , Triglycerides/blood , Adult , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/therapeutic use , Aged, 80 and over , Anticarcinogenic Agents/therapeutic use , Anticarcinogenic Agents/adverse effects , Hypertriglyceridemia/chemically inducedABSTRACT
BACKGROUND: Bilateral adrenal infarction is rare and only a small number of cases have been reported so far. Adrenal infarction is usually caused by thrombophilia or a hypercoagulable state, such as antiphospholipid antibody syndrome, pregnancy, and coronavirus disease 2019. However, adrenal infarction with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) has not been reported. CASE PRESENTATION: An 81-year-old man with a sudden severe bilateral backache presented to our hospital. Contrast-enhanced computed tomography (CT) led to the diagnosis of bilateral adrenal infarction. Previously reported causes of adrenal infarction were all excluded and a diagnosis of MDS/MPN-unclassifiable (MDS/MPN-U) was reached, which was considered to be attributed to adrenal infarction. He developed a relapse of bilateral adrenal infarction, and aspirin administration was initiated. Partial primary adrenal insufficiency was suspected as the serum adrenocorticotropic hormone level was persistently high after the second bilateral adrenal infarction. CONCLUSION: This is the first case of bilateral adrenal infarction with MDS/MPN-U encountered. MDS/MPN has the clinical characteristics of MPN. It is reasonable to assume that MDS/MPN-U may have influenced bilateral adrenal infarction development, considering the absence of thrombosis history and a current comorbid hypercoagulable disease. This is also the first case of recurrent bilateral adrenal infarction. It is important to carefully investigate the underlying cause of adrenal infarction once adrenal infarction is diagnosed, as well as to assess adrenocortical function.
Subject(s)
COVID-19 , Myelodysplastic-Myeloproliferative Diseases , Neoplasms , Male , Humans , Aged, 80 and over , Myelodysplastic-Myeloproliferative Diseases/diagnosis , Recurrence , MutationABSTRACT
Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.
Subject(s)
Hypophosphatemia , Lung Neoplasms , Osteomalacia , Small Cell Lung Carcinoma , Male , Humans , Middle Aged , Small Cell Lung Carcinoma/complications , Small Cell Lung Carcinoma/drug therapy , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Hypophosphatemia/etiology , Phosphates , Fibroblast Growth Factors , Adrenocorticotropic Hormone , Osteomalacia/etiologyABSTRACT
INTRODUCTION: This study assessed the performance of a new fully automated immunoassay for fibroblast growth factor (FGF) 23 (Determinar CL FGF23 CL) among healthy individuals and those with chronic hypophosphatemia compared with the previous assay (Kainos FGF23 KI). MATERIALS AND METHODS: A total of 380 serum samples from healthy participants were collected to determine the reference range of FGF23 levels with CL. A total of 200 serum samples from 22 hypophosphatemic patients were collected simultaneously to compare the difference in FGF23 levels between CL and KI. The Mann-Whitney U test and linear regression analysis were adopted to assess the differences and linearity between the two assays. RESULTS: The median FGF23 levels among healthy individuals was 31.7 (interquartile: 26.4-37.5) pg/mL. When the reference range was calculated as the mean ± 2 standard deviation (2SD), it was 16.1-49.3 pg/mL. A total of 363 individuals (96%) among normal cases fell in this range. Among 200 samples from patients with chronic hypophosphatemic disorder, the median FGF23 levels analyzed by CL and KI were 123.0 (90.2-237.7) and 172.5 (115.8-290.7) pg/mL. KI yielded significantly higher FGF23 values than CL (p < 0.001). A linear regression model revealed the correlation between KI (x) and CL (y), which had a slope of 0.76 with a y-intercept of -0.32 and high linearity (R2 = 0.99). CONCLUSION: The new measurement kit yielded lower FGF23 values when compared with the previous assay. Clinicians should consider this discrepancy when they assay intact FGF23 values with CL.
Subject(s)
Hypophosphatemia , Osteomalacia , Fibroblast Growth Factors , Health Status , Humans , Reference Values , Statistics, NonparametricABSTRACT
OBJECTIVE: To examine whether parathyroid hormone (PTH) is associated with mortality among U.S. adults. METHODS: This study included 8286 U.S. adults aged ≥20 years with a measurement of serum intact PTH from the National Health and Nutrition Examination Survey 2003-2006 linked to national mortality data through 2015. Multivariable Cox proportional hazard regression models were employed to estimate the adjusted hazard ratio (aHR) of all-cause and cause-specific (cardiovascular and cancer) mortality according to intact PTH levels (low or low-normal, <38; middle-normal, 38-56; high-normal, 57-74; high, >74 pg/mL). We also stratified the analyses by serum albumin-adjusted calcium and 25-hydroxy vitamin D (25OHD) levels. RESULTS: During a median follow-up of 10.1 years, the mean age was 49 years, and 48% were men. After adjusting for potential confounders, both the high-normal and high PTH groups showed higher risks of all-cause mortality than the low or low-normal PTH group (high-normal PTH, aHR, 1.28; 95% confidence interval [CI], 1.10-1.48; high PTH, aHR, 1.42; 95% CI, 1.19-1.69]. When stratified by calcium and 25OHD levels, the association between high PTH and mortality was also found among participants with albumin-adjusted calcium levels of ≥9.6 mg/dL (aHR, 1.53; 95% CI, 1.17-2.01) and those with 25OHD levels of ≥20 ng/mL (aHR, 1.46, 95% CI, 1.17-1.82). We found no evidence of the increased cause-specific mortality risks in the high PTH group. CONCLUSION: Higher PTH levels were associated with an increased risk of all-cause mortality, particularly among participants with albumin-adjusted calcium levels of ≥9.6 mg/dL or 25OHD levels of ≥20 ng/mL.
Subject(s)
Mortality , Parathyroid Hormone , Vitamin D , Adult , Calcifediol/blood , Calcium/blood , Female , Humans , Male , Middle Aged , Nutrition Surveys , Parathyroid Hormone/blood , United States , Vitamin D/bloodABSTRACT
The incidence of thyroid carcinoma has been increasing worldwide. This is interpreted as an increase in the incidental detection of papillary thyroid microcarcinomas (PTMCs). However, mortality has not changed, suggesting overdiagnosis and overtreatment. Prospective clinical trials of active surveillance for low-risk PTMC (T1aN0M0) have been conducted in two Japanese institutions since the 1990s. Based on the favorable outcomes of these trials, active surveillance has been gradually adopted worldwide. A task force on the management of PTMC in adults organized by the Japan Thyroid Association therefore conducted a systematic review and has produced the present position paper based on the scientific evidence concerning active surveillance. This paper indicates evidence for the increased incidence of PTMC, favorable surgical outcomes for low-risk PTMC, recommended criteria for diagnosis using fine needle aspiration cytology, and evaluation of lymph node metastasis (LNM), extrathyroidal extension (ETE) and distant metastasis. Active surveillance has also been reported with a low incidence of disease progression and no subsequent recurrence or adverse events on survival if conversion surgery was performed at a slightly advanced stage. Active surveillance is a safe and valid strategy for PTMC, because it might preserve physical quality of life and reduce 10-year medical costs. However, some points should be noted when performing active surveillance. Immediate surgery is needed for PTMC showing high-risk features, such as clinical LNM, ETE or distant metastasis. Active surveillance should be performed under an appropriate medical team and should be continued for life.
Subject(s)
Thyroid Cancer, Papillary/therapy , Thyroid Gland/pathology , Thyroid Neoplasms/therapy , Adult , Humans , Japan , Thyroid Cancer, Papillary/pathology , Thyroid Cancer, Papillary/surgery , Thyroid Gland/surgery , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery , Watchful WaitingABSTRACT
In the largest retrospective study of adrenal incidentalomas (AIs) in Japan between 1999 and 2004, adrenal tumors detected during secondary hypertension (HT) screening were included. The characteristics of patients with adrenal tumors detected during HT screening may differ from those of patients with AIs. This study aimed to compare the characteristics of patients with AIs with those of patients with adrenal tumors detected during HT screening. We retrospectively analyzed patients referred to our division for detailed examination of adrenal tumors between April 2009 and April 2017. When the purposes of imaging tests included HT screening, we defined adrenal tumors as HT associated, otherwise as strictly defined AIs. We reviewed data on age, sex, purpose and modality of imaging, location of tumor, tumor diameter, and hormonal evaluation. We identified 104 patients with HT-associated adrenal tumors and 413 with AIs. Patients with HT-associated adrenal tumors were younger (54.2 years vs. 61.7 years, p < 0.001) and had smaller tumor diameters (1.3 cm vs. 1.9 cm, p < 0.001), lower prevalence of nonfunctioning tumors (24.0% vs. 67.6%, p < 0.001), and higher prevalence of primary aldosteronism (58.7% vs. 4.8%, p < 0.001) than those with AIs. There were no differences in terms of tumor location and prevalence of subclinical Cushing's syndrome, Cushing's syndrome, and pheochromocytoma (18.3% vs. 16.0%, 7.7% vs. 8.0%, and 2.9% vs. 4.6%, respectively). In conclusion, patients with HT-associated tumors were younger and had a smaller tumor with higher prevalence of primary aldosteronism than those with AIs.
Subject(s)
Adrenal Gland Neoplasms/diagnosis , Hyperaldosteronism/diagnosis , Hypertension/diagnosis , Adrenal Gland Neoplasms/complications , Adrenal Gland Neoplasms/epidemiology , Adrenal Gland Neoplasms/pathology , Adult , Aged , Cushing Syndrome/complications , Cushing Syndrome/diagnosis , Cushing Syndrome/epidemiology , Diagnosis, Differential , Diagnostic Imaging/methods , Female , Humans , Hydrocortisone/metabolism , Hyperaldosteronism/complications , Hyperaldosteronism/epidemiology , Hypertension/epidemiology , Hypertension/etiology , Japan/epidemiology , Male , Middle Aged , Pheochromocytoma/complications , Pheochromocytoma/diagnosis , Pheochromocytoma/epidemiology , Prevalence , Retrospective StudiesABSTRACT
OBJECTIVE: Central hypothyroidism (CH) is a well-known adverse effect of bexarotene treatment for cutaneous T-cell lymphoma (CTCL). While concomitant levothyroxine therapy is recommended in these cases, associations between ethnic variation or susceptibility and bexarotene-induced CH have not yet been reported. This study aimed to characterize the kinetics and dose dependency of bexarotene-induced CH in Japanese patients. DESIGN AND PATIENTS: Sixty-six Japanese patients with CTCL were retrospectively investigated by evaluating thyroid function during the early phase of bexarotene therapy. RESULTS: At one week after bexarotene initiation, TSH and FT4 values significantly declined. However, this effect was not bexarotene dose-dependent at least at the dose of 96-320 mg/m2 . Approximately 1 month later, 61 patients exhibited hypothyroidism at a relatively low dose of bexarotene (average 251 mg/m2 /day). Forty-five study cases showed this effect at 1 week. Simple regression analyses indicated that higher pretreatment TSH values (at a cut-off value of 1.30:73% sensitivity, 57% specificity) or lower normal (within the lower half of the reference range) pretreatment FT4 values (84% sensitivity, 57% specificity) were predictive of hypothyroidism at 1 week. The remaining 21 cases showed euthyroidism at 1 week, at which TSH values may roughly predict their thyroid function at 1 month (at a cut-off value of 0.05:100% sensitivity, 80% specificity). CONCLUSIONS: Preventive treatment with levothyroxine is recommended for Japanese CTCL patients prior to bexarotene therapy. Minimally, it should be considered for patients with a pretreatment TSH above 1.30, a lower normal pretreatment FT4, or a TSH below 0.05 at 1 week.
Subject(s)
Bexarotene/adverse effects , Hypothyroidism/chemically induced , Adult , Aged , Aged, 80 and over , Bexarotene/therapeutic use , Female , Humans , Hypothyroidism/blood , Lymphoma, T-Cell, Cutaneous/blood , Lymphoma, T-Cell, Cutaneous/drug therapy , Male , Middle Aged , Regression Analysis , Retrospective Studies , Thyrotropin/blood , Thyroxine/bloodABSTRACT
Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.
Subject(s)
Endocrine System Diseases/chemically induced , Endocrine System Diseases/therapy , Immune System Diseases/chemically induced , Immune System Diseases/therapy , Immunologic Factors/adverse effects , Protein Kinase Inhibitors/adverse effects , Adrenal Gland Diseases/chemically induced , Adrenal Gland Diseases/therapy , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/immunology , Diabetes Mellitus/chemically induced , Diabetes Mellitus/immunology , Diabetes Mellitus/therapy , Endocrine System Diseases/diagnosis , Humans , Immune System Diseases/diagnosis , Immunologic Factors/therapeutic use , Japan , Parathyroid Diseases/chemically induced , Parathyroid Diseases/therapy , Protein Kinase Inhibitors/therapeutic use , Societies, Medical/organization & administration , Societies, Medical/standards , Thyroid Diseases/chemically induced , Thyroid Diseases/therapyABSTRACT
Primary hyperparathyroidism (PHPT) is a common endocrine disease. Although surgical treatment is curative in most cases, there are few alternative therapies for the hypercalcemia caused by PHPT. Cinacalcet is a positive allosteric modulator of the calcium sensing receptor and was conditionally approved in Japan in 2014 to treat PHPT cases. However, there have been few reports on the outcomes. In our present study, we investigated the efficacy and safety of cinacalcet in 61 PHPT patients who were treated with this agent at our hospital between January 2014 and March 2017. The corrected serum Ca and intact PTH levels were significantly reduced by this treatment, whereas the serum phosphorus levels significantly increased. There were no significant differences in the eGFR or urinary Ca to urinary creatinine ratio between baseline and the maintenance phase. In terms of bone mineral density, there were significant increases observed in the 16 cases for whom a baseline value was available, 11 of whom had been treated for osteoporosis. The most common adverse events from cinacalcet treatment were gastrointestinal symptom, such as nausea and appetite loss. Other adverse events included severe dehydration due to hypercalcemia, myalgia, hypocalcemia, and increased urinary calcium excretion. Seven patients were switched to surgical treatment, and the drug was discontinued in 9 other patients, due to adverse effects. Our present study findings demonstrate that cinacalcet is an effective therapeutic option for PHPT from the perspective of hypercalcemia improvement but that adverse gastrointestinal effects of this drug occur at a frequency of about 10%.
Subject(s)
Cinacalcet/therapeutic use , Hyperparathyroidism, Primary/drug therapy , Adult , Aged , Aged, 80 and over , Bone Density/drug effects , Calcium/blood , Cinacalcet/adverse effects , Female , Humans , Hypercalcemia/blood , Hypercalcemia/chemically induced , Hyperparathyroidism, Primary/blood , Male , Middle Aged , Nausea/blood , Nausea/chemically induced , Retrospective Studies , Treatment OutcomeABSTRACT
Ectopic ACTH syndrome (EAS) due to a prostate small cell carcinoma (SCC) is very rare with only 26 cases reported to date and has a poor prognosis. We here describe another case of this disorder that was clinically typical based on prior reports as it showed hypercortisolemia and severe hypokalemia with multiple metastasis. However, our current case of prostate SCC causing EAS is the first to display negative immunostaining for ACTH despite detectable POMC mRNA expression in the primary lesion. ACTH immunonegativity is thought to be associated with a more aggressive disease course and a poorer prognosis although there are few studies of the underlying mechanisms. We explored two possibilities for this finding in our current patient: aberrant POMC processing prevented immunodetection with an anti-ACTH antibody; and the ACTH content per cell was below the threshold for immunodetection due to its rapid secretion or low synthesis. The aberrant processing theory was thought to be less likely because of immunonegative findings even using anti-POMC/ACTH antibodies. As the plasma ACTH levels in our patient were comparable with those reported for previous immunopositive prostate EAS cases, we speculated that the depletion of ACTH may be caused not only by rapid secretion but also by low production levels as a sign of de-differentiation. De-differentiation may therefore explain the mechanism underlying the negative correlation between immunoreactivity for ACTH in EAS and disease aggressiveness. We believe that our present findings will be of use in future prospective studies aimed at confirming the mechanism of immunonegativity.
Subject(s)
ACTH Syndrome, Ectopic/etiology , Carcinoma, Small Cell/complications , Prostate/metabolism , Prostatic Neoplasms/complications , ACTH Syndrome, Ectopic/metabolism , ACTH Syndrome, Ectopic/pathology , Adrenocorticotropic Hormone/blood , Aged , Carcinoma, Small Cell/metabolism , Carcinoma, Small Cell/pathology , Humans , Male , Prostate/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathologyABSTRACT
Disease-causing mutations in G protein-coupled receptor (GPCR) genes, including the V2 vasopressin receptor (V2R) gene, often cause misfolded receptors, leading to a defect in plasma membrane trafficking. A novel V2R mutation, T273M, identified in a boy with partial nephrogenic diabetes insipidus (NDI), shows intracellular localization and partial defects similar to the two mutants we described previously (10). Although non-peptide V2R antagonists have been shown to rescue the membrane localization of V2R mutants, their level of functional rescue is weak. Interestingly, it has been reported that a non-peptide agonist, OPC51803, activates misfolded V2R mutants intracellularly without degradation, thus potentially serving as a therapeutic agent against NDI (14). In our current experiments, however, a peptide antagonist blocked arginine vasopressin (AVP)- or OPC51803-stimulated cAMP accumulation both in COS-7 and MDCK cells, suggesting that OPC51803 mainly stimulates cell surface V2R mutants. In addition, our analyses revealed that OPC51803 works not only as a non-peptide agonist that causes activation/ß-arrestin-dependent desensitization of V2R mutants expressed at the plasma membrane but also as a pharmacochaperone that promotes the endoplasmic reticulum-retained mutant maturation and trafficking to the plasma membrane. The ratio of the pharmacochaperone effect to the desensitization effect likely correlates negatively with the residual function of the tested mutants, suggesting that OPC5 has a more favorable effect on the V2R mutants with a less residual function. We speculated that the canceling of the desensitization effect of OPC51803 by the pharmacochaperone effect after long-term treatment may produce sustainable signaling, and thus pharmacochaperone agonists such as OPC51803 may serve as promising therapeutics for NDI caused by misfolded V2R mutants.
Subject(s)
Benzazepines/pharmacology , Diabetes Insipidus, Nephrogenic , Mutation , Pyrrolidines/pharmacology , Receptors, Vasopressin , Animals , COS Cells , Chlorocebus aethiops , Diabetes Insipidus, Nephrogenic/diet therapy , Diabetes Insipidus, Nephrogenic/genetics , Diabetes Insipidus, Nephrogenic/metabolism , Dogs , HEK293 Cells , Humans , Madin Darby Canine Kidney Cells , Male , Receptors, Vasopressin/agonists , Receptors, Vasopressin/genetics , Receptors, Vasopressin/metabolismABSTRACT
Vitamin D-dependent rickets type 2A (VDDR2A) is a rare inherited disorder with decreased tissue responsiveness to 1,25-dihydroxyvitamin D [1,25(OH)2D], caused by loss of function mutations in the vitamin D receptor (VDR) gene. Approximately 50 types of mutations have been identified so far that change amino acids in either the N-terminal DNA binding domain (DBD) or the C-terminal ligand binding domain (LBD) of the VDR protein. The degree of responsiveness to 1,25(OH)2D varies between patients with VDDR2A, which may depend on their residual VDR function. In this report, we describe a female patient with VDDR2A caused by an early stop codon (R30X) in the VDR gene that resulted in a severely truncated VDR protein. She developed alopecia and bowed legs within a year after birth and was diagnosed with rickets at the age of 2. She had been treated with active vitamin D and oral calcium supplementation until 22 years of age, when she developed secondary hyperparathyroidism and high bone turnover. The genetic diagnosis of VDDR2A promoted the discontinuation of active vitamin D treatment in favor of monotherapy with oral calcium supplementation. We observed amelioration of the secondary hyperparathyroidism and normalization of bone metabolic parameters within 6 years.
Subject(s)
Bone and Bones/metabolism , Calcium, Dietary/therapeutic use , Dietary Supplements , Familial Hypophosphatemic Rickets/diet therapy , Adult , Alopecia/etiology , Codon, Terminator , Familial Hypophosphatemic Rickets/genetics , Familial Hypophosphatemic Rickets/metabolism , Familial Hypophosphatemic Rickets/physiopathology , Female , Humans , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/prevention & control , Mutation , Receptors, Calcitriol/genetics , Treatment Outcome , Young AdultABSTRACT
In the classical two-state model, G protein-coupled receptors (GPCRs) are considered to exist in equilibrium between an active and an inactive conformation. Thus, even at the resting state, some subpopulation of GPCRs is in the active state, which underlies the basal activity of the GPCRs. In this review, we discuss inverse agonists, which are defined as GPCR ligands that shift the equilibrium toward the inactive state and thereby suppress the basal activity. Theoretically, if constitutive activation plays an essential role in the pathogenesis of a disease, only inverse agonists, and not neutral antagonists, can reverse this pathophysiological activation. Although many pharmacological examples of inverse agonism have been identified, its clinical importance is still unclear and debated. Thus, even though inverse agonism of angiotensin receptor blockers (ARBs) has been discussed for more than 10 years, its clinical relevance remains to be completely clarified.
Subject(s)
Drug Inverse Agonism , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/antagonists & inhibitors , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Animals , Heart Failure/drug therapy , Heart Failure/metabolism , Humans , Ligands , Receptor, Angiotensin, Type 1/agonists , Receptor, Angiotensin, Type 1/metabolism , Receptors, G-Protein-Coupled/physiology , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
Metastatic bone disease is one of the most common complications of advanced cancers. Pathological fractures, spinal cord compression, and radiotherapy or surgery to the bone are collectively called skeletal-related events (SREs), which cause severe pain, increase hospitalization rates, and impair the quality of life (QOL) of patients with bone metastases. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK pathway is critical in the progression of bone metastases. Previous studies have demonstrated that an anti-RANKL antibody (denosumab) was superior to zoledronic acid in prolonging time to first SRE in patients with bone metastases from prostate and breast cancers. However, severe hypocalcemic events occur more frequently after treatment with denosumab compared with zoledronic acid. In this study, 368 administrations of denosumab in 219 patients with metastatic bone disease from solid tumors were analyzed to clarify the risk factors for developing hypocalcemia. The results showed that grade 2/3 hypocalcemia was observed in 10.4% of the total number of denosumab administrations. Patients with higher baseline serum ALP, higher performance status (PS), or gastric cancer were at higher risk for developing hypocalcemia. The cut-off value for ALP to predict denosumab-related hypocalcemia was 587 U/L with a sensitivity of 0.77 and a specificity of 0.81. Close monitoring of serum calcium, especially after the first treatment with denosumab, is strongly recommended in these patients.
Subject(s)
Alkaline Phosphatase/blood , Bone Neoplasms/secondary , Denosumab/adverse effects , Hypocalcemia/chemically induced , Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Bone Density Conservation Agents/adverse effects , Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/blood , Bone Neoplasms/drug therapy , Denosumab/therapeutic use , Female , Humans , Hypocalcemia/blood , Male , Middle Aged , Neoplasms/blood , Neoplasms/drug therapy , Retrospective Studies , Risk Factors , Up-Regulation , Young AdultABSTRACT
RATIONALE: The clinical problem of loss of ß-adrenergic receptor (ß-AR) response, both in the pathogenesis of heart failure and during therapeutic application of ß-agonists, is attributable, at least in part, to desensitization, internalization, and downregulation of the receptors. In the regulation of ß-AR signaling, G protein-coupled receptor kinase 2 (GRK2) primarily phosphorylates agonist-occupied ß-ARs, and this modification promotes desensitization, internalization, and downregulation of ß-ARs. It has been demonstrated that GRK2 is inhibited by its S-nitrosylation. However, compounds that induce S-nitrosylation, such as S-nitrosoglutathione, simultaneously generate NO, which has been demonstrated to operate for cardiovascular protection. OBJECTIVE: We examine whether S-nitrosylation without NO generation inhibits desensitization of ß(2)-AR by GRK2. We thus aim to synthesize compounds that specifically induce S-nitrosylation. METHODS AND RESULTS: We have developed water-soluble N-nitrosamines that have S-nitrosylating activity but lack NO-generating activity. These compounds, at least partly, rescue ß-AR from desensitization in HEK 293 cells expressing FLAG-tagged human ß(2)-AR and in rat cardiac myocytes. They inhibit isoproterenol-dependent phosphorylation and internalization of ß(2)-AR. Indeed, they nitrosylate GRK2 in vitro and in cells, and their S-nitrosylation of GRK2 likely underlies their inhibition of ß(2)-AR desensitization. CONCLUSIONS: Compounds that induce S-nitrosylation without NO release inhibit GRK2 and attenuate ß(2)-AR desensitization. Developing water-soluble drugs that specifically induce S-nitrosylation may be a promising therapeutic strategy for heart failure.
Subject(s)
Nitric Oxide , Nitrosamines/metabolism , Nitrosamines/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Water/physiology , Animals , HEK293 Cells , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Nitric Oxide/metabolism , Nitrosamines/chemistry , Rats , Solubility/drug effects , Water/chemistryABSTRACT
The classical model of G protein-coupled receptor (GPCR) activation is the two-state model, in which the GPCR exists in equilibrium between an active and inactive state. Based on this model, GPCR ligands have been classified as agonists, inverse agonists, or antagonists depending on their actions in shifting this equilibrium. Recently, however, accumulating evidence has indicated that GPCRs may exist in multiple active and inactive conformational states. In this situation, each ligand recognizes and stabilizes a specific conformation of the GPCR, leading to a set of specific biological effects. Based on this new model, a unique agonist or a combination of the usual agonist and an allosteric modulator may enable activation of a specific signaling pathway via a GPCR that activates multiple signals (biased agonism, functional selectivity). The calcium-sensing receptor autoantibody that we have identified in the serum of a patient with acquired hypocalciuric hypercalcemia (AHH) is the first example of a biased allosteric modulator of a GPCR working in a pathophysiological context. Our findings may indicate the presence of physiological allosteric modulators and provide new directions for the future drug development.