Cardiovascular Outcomes of KCNJ5 Mutated Aldosterone-Producing Adenoma: A Systematic Review.

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.

Clinical Factors Affecting Daily Dosage of Desmopressin Orally Disintegrating Tablets in Arginine Vasopressin Deficiency.

CONTEXT: Desmopressin orally disintegrating tablets (ODTs) are widely used to treat arginine vasopressin deficiency (AVP-D). However, limited information is available on the dosage regimen; the dosage for each patient is selected based on their response to the initiation dose. OBJECTIVE: To investigate the relationships between clinical characteristics and the daily dose of ODTs and to identify factors that affect ODT dosages. METHODS: This retrospective study included 209 adult patients with AVP-D. Patients were administered ODTs sublingually and instructed to restrict eating and drinking for 30 minutes after taking ODTs using a patient leaflet. ODT dose titration was conducted during hospitalization with close monitoring of urine output, body weight, and serum sodium levels. Multivariable linear regression models were applied to identify clinical factors associated with the daily dose of ODTs at discharge. We also evaluated the dosage at 1 year in 134 patients who were followed up in our hospital. RESULTS: The median daily dose of ODTs at discharge was 90 µg (IQR 60-120 µg). Multivariable linear regression models identified sex, age, and estimated creatinine clearance (eCCr) as significant factors associated with the daily dose of ODTs, with eCCr having the strongest effect. After excluding patients recovering from AVP-D, 71% of those followed up at our hospital took the same daily dose at 1 year after discharge. CONCLUSION: To achieve the safe and stable treatment of AVP-D, the daily dose of ODT needs to be selected based on a patient's sex, age, and eCCr under appropriate sublingual administration by patient education.

The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult-Onset Hypophosphatasia.

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue-nonspecific alkaline phosphatase. Adult-onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first-line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64-year-old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6-minute walk test (525 to 606 m). The EQ-5D-5L index was also improved (0.757 to 0.895). Within a follow-up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 µM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

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.

Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report.

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.

Clinical performance of a new intact FGF23 immunoassay in healthy individuals and patients with chronic hypophosphatemia.

While the positive association between automated intact fibroblast growth factor (FGF) 23 measurement kit (Determinar CL FGF23 [CL]) and the former assay (Kainos [KI]), and clinical utility of CL was well established, the clinical performance of Medfrontier FGF23 (MED), which was the manual intact FGF23 measurement kit with same antibody set as CL, has not yet been validated. Therefore, this study aims to compare MED FGF23 levels to KI FGF23 levels. A total of 380 samples were collected from healthy individuals, and 200 samples were collected from 20 patients with chronic hypophosphatemia. The intact FGF23 level of each sample was measured by KI and MED. Among the healthy individuals, the reference range of MED FGF23 levels was 18.6-59.8 pg/mL when calculated as the average ± 2 standard deviations. When compared with KI FGF23 levels, MED FGF23 levels were lower than KI levels both among samples from healthy individuals (KI FGF23, 40.9 [interquartile (IQR), 31.1-50.6]; MED FGF23, 38.0 [IQR, 31.5-45.7]; p value = 0.02) and among samples from patients with chronic hypophosphatemia (KI FGF23, 172.5 [IQR, 115.8-290.7]; MED FGF23, 130.2 [IQR, 93.6-247.0]; p value = 0.003). The linear regression analysis showed that the correlation between KI FGF23 and MED FGF23 was interpreted as a slope of 0.83 with a y-intercept of 0.53, revealing good linearity (R2 = 0.99). This study showed that the discrepancy between KI and MED was very similar to the previously reported data between KI and CL.

Effect of Conventional Treatment on Dental Complications and Ectopic Ossifications Among 30 Adults With XLH.

CONTEXT: Conventional treatment of X-linked hypophosphatemia (XLH) was reported to prevent dental complications, but whether the preventive effect was different among different types of teeth, including anterior teeth and molar teeth, is uncertain. Evidence of the preventive effect of conventional treatment on ectopic ossifications is also limited. OBJECTIVE: To compare dental complications and ectopic ossifications among adults with XLH with early (<5 years old) or late (≥5 years old) conventional treatment. METHODS: This retrospective observational study included a total of 30 adults with XLH; orthopantomograms, spinal computed tomography scans, and X-rays of hip/knee joints were studied. Dental complications, including the decayed, missing, filled (DMF) index and devitalized teeth, apical periodontitis, and periodontitis, were evaluated. The ossification of the anterior/posterior longitudinal ligament and yellow ligament indexes (OA/OP/OY indexes) and the sum of the OA/OP/OY indexes (OS index) were utilized to evaluate the severity of spinal ligament ossification. The severity of the hip/knee osteophytes was evaluated using the Kellgren-Lawrence (KL) classification. RESULTS: The number of sound teeth was significantly lower and the DMF index was significantly higher in patients with late treatment. The severity of dental complications in the anterior tooth and molar tooth, OA/OP/OY/OS index, and KL grade were not significantly different among patients with early treatment and those with late treatment. CONCLUSION: Early treatment could prevent dental complications but did not prevent ectopic ossification in adult patients with XLH. The difference in the preventive effect was not observed among different types of teeth.

Utility of Multimodality Approach Including Systemic FGF23 Venous Sampling in Localizing Phosphaturic Mesenchymal Tumors.

Context: Tumor-induced osteomalacia (TIO) is one of the most common forms of acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemia and is usually caused by phosphaturic mesenchymal tumors (PMTs). Although the complete resection of PMTs can cure TIO, preoperative localization of tumors by standard imaging modalities is often challenging. In addition to 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (FDG-PET) and 111In-pentetreotide scintigraphy (SRS), systemic FGF23 venous sampling (FGF23VS) has been used to help localize PMTs in specialized institutions. Objective: This study aimed to evaluate the diagnostic performance of each imaging test and their combinations in localizing PMTs. Methods: In an observational retrospective study of patients with adult-onset FGF23-related osteomalacia who underwent all 3 imaging studies (FDG-PET, SRS, and FGF23VS), the rate of successful preoperative localization of the tumors was evaluated only in the patients with pathological diagnoses of PMTs, considering the possibility that pathogenesis of patients without identified tumors might be due to other causes such as late-onset hereditary FGF23-related hypophosphatemia. Results: A total of 30 Japanese patients with TIO (median age, 60 years [range, 28-87 years]; 10 women [33.3%]) were included in the study. The success rate of preoperative localization for each test and combinations of 2 or 3 tests among 18 patients with PMTs was as follows: 72% (FDG-PET), 72% (SRS), 94% (FGF23VS), 89% (FDG-PET, SRS), 100% (FDG-PET, FGF23VS), 94% (SRS, FGF23VS), and 100% (FDG-PET, SRS, and FGF23VS). Conclusion: We observed the highest localization rate of PMTs in patients with identified PMTs with the combination of FDG-PET and FGF23VS.

Incidence of ossification of the spinal ligaments in acromegaly patients.

Some previous case reports have implied a relationship between acromegaly and ossification of the spinal ligaments. However, there have been no reports of a case series exploring the incidence of ossification of the spinal ligaments in patients with acromegaly. To this end, computed tomography (CT) of the spine in 10 consecutive patients with acromegaly was examined in this study. Five out of 10 patients had ossification of the spinal ligaments. Among them, two patients had ossification of the posterior longitudinal ligament (OPLL), which was noticeably higher than the prevalence of OPLL in the general adult population (1.9-4.3 %). Body mass index was significantly higher in the group with spinal ligament ossification (p = 0.03), but there were no significant differences in age, sex, serum phosphate, albumin-adjusted calcium, growth hormone (GH), standard deviation of insulin-like growth factor-1 (IGF-1), or the incidence of diabetes mellitus between the groups with or without ossification of the spinal ligaments. The ossification index (OS index) was used to determine the severity of spinal ligament ossification, and there were no significant correlations between the OS index and GH or IGF-1 (p = 0.51 and 0.75, respectively). This study was the first to report a high prevalence of spinal ossification in patients with acromegaly. In conclusion, this study suggested a possible association between acromegaly and ossification of the spinal ligaments, although the number of patients was insufficient to draw a conclusion. Acromegaly patients should be tested to confirm, or rule out, spinal ossification, and further studies to clarify the underlying mechanism of spinal ossification in acromegaly patients are warranted.

Machine Learning-Based Prediction of Elevated PTH Levels Among the US General Population.

CONTEXT: Although elevated parathyroid hormone (PTH) levels are associated with higher mortality risks, the evidence is limited as to when PTH is expected to be elevated and thus should be measured among the general population. OBJECTIVE: This work aimed to build a machine learning-based prediction model of elevated PTH levels based on demographic, lifestyle, and biochemical data among US adults. METHODS: This population-based study included adults aged 20 years or older with a measurement of serum intact PTH from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006. We used the NHANES 2003 to 2004 cohort (n = 4096) to train 6 machine-learning prediction models (logistic regression with and without splines, lasso regression, random forest, gradient-boosting machines [GBMs], and SuperLearner). Then, we used the NHANES 2005 to 2006 cohort (n = 4112) to evaluate the model performance including area under the receiver operating characteristic curve (AUC). RESULTS: Of 8208 US adults, 753 (9.2%) showed PTH greater than 74 pg/mL. Across 6 algorithms, the highest AUC was observed among random forest (AUC [95% CI] = 0.79 [0.76-0.81]), GBM (AUC [95% CI] = 0.78 [0.75-0.81]), and SuperLearner (AUC [95% CI] = 0.79 [0.76-0.81]). The AUC improved from 0.69 to 0.77 when we added cubic splines for the estimated glomerular filtration rate (eGFR) in the logistic regression models. Logistic regression models with splines showed the best calibration performance (calibration slope [95% CI] = 0.96 [0.86-1.06]), while other algorithms were less calibrated. Among all covariates included, eGFR was the most important predictor of the random forest model and GBM. CONCLUSION: In this nationally representative data in the United States, we developed a prediction model that potentially helps us to make accurate and early detection of elevated PTH in general clinical practice. Future studies are warranted to assess whether this prediction tool for elevated PTH would improve adverse health outcomes.

A Case of 123I-Metaiodobenzylguanidine Scintigraphy-Negative Pheochromocytoma with a Tumor-Developing Mutation in the RET Gene.

Pheochromocytoma (PCC) is rare catecholamine-producing endocrine tumor that metastasizes in approximately 10% of cases. As a functional imaging of PCC, 123I-metaiodobenzylguanidine (MIBG) scintigraphy was established, and some cases of PCC exhibit negative accumulation on MIBG scintigraphy, indicating a high risk of metastasis. Additionally, germline genetic variants of PCC are evident in approximately 30% of cases, although the genotype-phenotype correlation in PCC, especially the association between genetic mutations and MIBG scintigraphy, remains unclear. A 33-year-old man was admitted to our hospital for further examination for hypertension. He was diagnosed with sporadic PCC, and left adrenalectomy was performed. The adrenal tumor was negative on MIBG scintigraphy. Histology of the tumor revealed a moderately differentiated PCC. Target gene testing revealed a mutation in RET (c.2071G > A). This mutation has been reported to be a tumor-developing gene involved in the pathogenesis of PCC. Moreover, the RET mutation is the only gene mutation reported in a previous study of PCC with negative results on MIBG scintigraphy, except for the SDHB gene mutation, which is a common mutation in metastatic PCC. Correctively, the present RET gene mutation may be associated to MIBG-scintigraphy negative PCC and its pathophysiology. Clinicians should follow such cases more cautiously in clinical practice.

Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance.

Tumor-induced osteomalacia (TIO) is an acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia caused by phosphaturic mesenchymal tumors (PMTs) developed in the bone or soft tissue. Diagnostic delay should be addressed, and ideal techniques to localize PMTs and efficient treatment options should be explored to improve the outcomes of this rare disease. To clarify the detailed clinical course and outcomes of TIO patients, retrospective questionnaire surveys were conducted among physicians from the Japanese Society for Bone and Mineral Research (JSBMR) and the Japan Endocrine Society (JES). The primary survey collected the number of TIO patients between January 2007 and December 2018. The secondary survey aimed to obtain the detailed characteristics, laboratory data, and outcomes. Eighty-eight patients (52 males, mean: 52 years old) were included, and 24 patients were clinically diagnosed with TIO without localized PMTs. The median duration from the onset to detection of high FGF23 levels was 3.4 years, with 77 patients being initially misdiagnosed. Among the methods used to detect small, localized PMTs (≤10 mm), fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography and somatostatin receptor scintigraphy were less sensitive than somatostatin receptor positron emission tomography/computed tomography (SRPET/CT). Systemic venous sampling (SVS) of FGF23 was performed in 53 patients; among them, SVS was considered useful for detecting localized PMTs in 45 patients with diverse tumor sizes. Finally, 45 patients achieved biochemical remission by surgery, 39 patients continued pharmaceutical treatment, including burosumab (11 patients), and four patients died. These results encouraged us to further increase the awareness of TIO and to improve the accessibility of SRPET/CT and SVS. Further evidence about the efficacy of new pharmaceutical treatments is awaited. © 2022 American Society for Bone and Mineral Research (ASBMR).

Comparison of Echocardiographic Changes Between Surgery and Medication Treatment in Patients With Primary Aldosteronism.

Background Primary aldosteronism can cause cardiac dysfunction, including left ventricular hypertrophy, left ventricular diastolic dysfunction, and left atrial enlargement. A few studies have compared the cardioprotective effects between surgery and medication for primary aldosteronism, although most have not adjusted for baseline disease status. In this study, we investigated the difference in cardiovascular outcomes between surgery and medication treatment for primary aldosteronism after adjusting for baseline clinical characteristics, including aldosterone level and pretreatment echocardiographic information. Methods and Results We retrospectively analyzed 220 patients diagnosed with primary aldosteronism who underwent adrenalectomy (n=144) or medication treatment (n=76) between 2009 and 2019. Echocardiographic changes were evaluated pretreatment and 1 year posttreatment. The surgery group had lower potassium, lower plasma renin activity, and higher plasma aldosterone concentration than the medication group, indicating a severe primary aldosteronism phenotype in the former. The decrease in left ventricular mass index after treatment was significantly greater in the surgery group than in the medication group (P=0.047). However, this relationship was not noted after multivariable regression analysis (standard ß=-0.08, P=0.17). Additionally, decreased parameter values related to left ventricular diastolic dysfunction and left atrial enlargement were not different between the groups. Pretreatment echocardiographic values were most associated with changes in all echocardiographic parameters. The findings were consistent in the propensity score-matched analysis. Conclusions This study's findings suggest that there is no difference in cardioprotective efficacy between surgical and medication treatment under similar disease severity; however, it should be considered that several study participants with severe hyperaldosteronism were managed surgically.

Two Cases of Thyrotoxicosis and Euglycemic Diabetic Ketoacidosis Under Sodium-glucose Transport Protein 2 Inhibitor Treatment.

Thyrotoxicosis and sodium-glucose transport protein 2 inhibitors (SGLT2is) are associated with the induction of euglycemic diabetic ketoacidosis (euDKA). We herein report two cases of euDKA in patients with diabetes mellitus wherein both thyrotoxicosis and SGLT2i treatment were the underlying causes. One patient developed thyrotoxicosis during the course of type 2 diabetes mellitus, whereas the other patient was suspected of developing slowly progressive insulin-dependent diabetes mellitus during the course of Graves' disease. Although such cases are rare, there is some concern that similar cases may occur because of the increased frequency of SGLT2i use in recent years.

A Case of Methimazole-Induced Acute Pancreatitis With an HLA Allele Causing Antithyroid Drug-Induced Agranulocytosis.

Among the side effects of methimazole (MMI) for the treatment of Graves' disease, MMI-induced acute pancreatitis (MIP) is a rare adverse reaction, with only 7 cases being reported to date. However, 2 large-scale population-based studies recently revealed that the risk of MIP was significantly higher, ranging from 0.02% to 0.56%. Although MIP is common in middle-aged and elderly Asian women, its pathogenesis remains largely unknown. We herein present a case of a 72-year-old Japanese woman with Graves' disease who developed MIP 12 days after the initiation of MMI. The MMI was discontinued, the patient was switched to propylthiouracil (PTU) therapy, and pancreatitis gradually resolved. Serological human leukocyte antigen (HLA) typing identified HLA-DRB1*08:03:02. This HLA allele was previously detected in a patient with MIP and is one of the major risk factors for agranulocytosis induced by antithyroid drugs, including PTU as well as MMI. In cases of MIP, PTU is being considered as an alternative to MMI; however, its safety needs further investigation and patients require close monitoring after the switch to PTU. Further studies are warranted, particularly on the relationship between MIP and the presence of HLA alleles causing antithyroid drug-induced agranulocytosis.

Characteristics of aldosterone-producing adenomas in patients without plasma renin activity suppression.

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] µg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] µ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected.

Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis.

Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77- and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wild-type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).

Intra-individual association between C-reactive protein and insulin administration in postoperative lumbar spinal canal stenosis patients: A retrospective cohort study.

The association of intra-individual variability in insulin requirements with C-reactive protein levels among acute phase patients remains unclear. This retrospective cohort study aimed to evaluate this association. Patients with type 2 diabetes undergoing surgery for lumbar spinal canal stenosis were included in the study. We analyzed 286 records of 49 patients using the linear mixed effects model. The model showed C-reactive protein levels to be significantly associated with insulin requirements, with an effect size of 0.60 U/day for an elevation of 1 mg/dL. The effect size was increased in patients with higher hemoglobin A1c levels. Our findings imply that C-reactive protein levels could be a useful clinical biomarker when blood glucose levels are controlled in acute phase patients.

A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia.

A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL. Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy. His CPR levels gradually decreased and were depleted within 1 week. We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission. Hence, the possibility of FT1DM in hyperglycemic patients undergoing nivolumab treatment should not be excluded, even with a preserved CPR level.