Journal of Clinical Endocrinology & Metabolism最新文献

Context: A continuum of non-suppressible aldosterone production has been demonstrated in normotensive individuals, termed subclinical primary aldosteronism (PA), and is consistently associated with increased risk for developing hypertension and cardiovascular disease. The hormonal mechanisms accounting for subclinical PA are not well understood.

Methods: To quantify the magnitude of subclinical PA, prospectively recruited normotensive participants (n = 75) had their maximally suppressed plasma aldosterone assessed after maintaining supine posture following an oral sodium loading protocol. To investigate the endocrine mechanisms involved with this continuum, multiple maneuvers were conducted to evaluate: (i) natriuretic peptide physiology (N-terminal pro B-type natriuretic peptide [NT-proBNP] suppression and stimulation using dietary sodium modulation); (ii) angiotensin II (AngII)-dependent aldosterone production (via dietary sodium restriction and via infusion of exogenous AngII); (iii) AngII-independent aldosterone production (via saline suppression test [SST]); and (iv) ACTH-mediated aldosterone production (via dexamethasone suppression test and ACTH-stimulation test).

Results: Greater magnitude of subclinical PA was associated with lower basal NT-proBNP (P-trend < .01) and blunted stimulation of NT-proBNP following sodium loading (P-trend = .023). The magnitude of subclinical PA was also associated with greater AngII-dependent (P-trend < .001) and AngII-independent (P-trend < .001) aldosterone production and paralleled the severity of ACTH-mediated aldosterone production (P-trends < .001). Following SST, 24.2% of participants had a post-saline aldosterone greater than 10 ng/dL and 72.7% had a post-saline aldosterone greater than 6 ng/dL, confirming that the continuum of subclinical PA included overt PA pathophysiology within these normotensive participants.

Conclusion: These findings demonstrate that the pathophysiologic continuum of subclinical PA in normotensive people is characterized by natriuretic peptide insufficiency and heightened aldosterone responses to both AngII and ACTH. These early maladaptive hormonal changes provide mechanistic explanations for the role of subclinical PA in the pathogenesis of hypertension.

Objective: The menopause transition (MT) may substantially contribute to increased systemic inflammation in later life, regardless of aging. We characterized inflammation trajectories over the MT and determined their associations with premenopausal obesity and race/ethnicity.

Methods: Data comprising 15 follow-up visits from Study of Women's Health Across the Nation participants who had a known date of their final menstrual period (FMP) and at least 3 measures of high-sensitivity C-reactive protein (hs-CRP) (n = 1470) or IL-6 (n = 779) were evaluated using group-based trajectory modeling and piecewise linear mixed-effects models.

Results: Based on 21 years of follow-up spanning the MT, we identified 3 trajectory groups for each inflammatory biomarker: (1) Low-Rise (hs-CRP = 27.2%; IL-6 = 36.0%); (2) Medium-Stable (hs-CRP = 41.9%) or Medium-Rise (IL-6 = 45.2%); and (3) High-Decline (hs-CRP = 30.9%) or High-Stable (IL-6 = 18.8%). The Low-Rise for both hs-CRP and IL-6 and the Medium-Rise for IL-6 trajectories showed significant increases as early as 1 year before to as late as 3 years after the FMP. The other trajectories showed either no change, or a decline around the FMP. Chinese and/or Japanese women were more likely to follow the Low-Rise hs-CRP and IL-6 trajectories, whereas Black women were more likely to follow the High-Decline hs-CRP and High-Stable IL-6 trajectories. Being overweight or obese was associated with the High-Decline hs-CRP and High-Stable IL-6 trajectories.

Conclusions: Midlife women experience distinct patterns of change in hs-CRP and IL-6 over the MT. Subgroups entering the MT with low-to-medium inflammation levels, particularly for IL-6, showed rises close to the FMP, supporting a contribution of menopause in progression of systemic inflammation.

Context: Electrolytes are essential for mineral and bone metabolism. However, their associations with fracture risk among older adults have not been extensively studied.

Objective: This work aimed to examine the associations of serum sodium, potassium, magnesium, calcium, and phosphorus levels with the risk of fracture.

Methods: A prospective cohort study of a US community comprised 5499 older adults from the Atherosclerosis Risk in Communities Study who completed visit 5 in 2011 to 2013. The analysis was replicated in 11 708 middle-aged adults who completed visit 2 in 1990 to 1992. Exposure included serum levels of sodium, potassium, magnesium, calcium, and phosphorus. The main outcome measure included hospitalization with fracture ascertained through diagnostic codes on hospital discharge records.

Results: In the visit 5 cohort (mean age, 75.4 years), multivariable Cox models with restricted cubic spline terms showed significant associations of lower sodium, magnesium, and calcium levels, and higher phosphorus levels with an increased risk of fracture. In clinical categories, this association remained significant for hyponatremia (≤135 vs 135-145 mEq/L) but not for hyperphosphatemia (≥4.5 vs 2.5-4.5 mg/dL) (HRs, 1.85 [95% CI, 1.22-2.81] and 2.18 [95% CI, 0.99-4.78], respectively). In the visit 2 cohort (mean age, 56.9 years), a significant association was observed for higher phosphorus levels, but not for other electrolytes, although findings were overall consistent.

Conclusion: In this community-based cohort, lower sodium, magnesium, and calcium levels, as well as higher phosphorus levels, were associated with greater fracture risk. These findings support the etiological link of serum electrolyte levels with the risk of fracture.

Context: The triglyceride-glucose (TyG) index is a reliable marker of insulin resistance. Although the TyG index is useful for identifying individuals at a high risk of future cardiovascular events and mortality in the general population, its clinical impact on young adults remains unclear.

Objective: This study aimed to investigate the association between the TyG index and mortality in young individuals.

Methods: We enrolled 6 667 138 individuals aged 20-39 years who underwent Korean national health screening between 2009 and 2012. Participants were categorized into quartiles based on their TyG indices. The study outcomes included all-cause and cause-specific mortality associated with cardiovascular events, cancer, and respiratory diseases.

Results: During a median follow-up duration of 10.7 years, 41 004 (0.6%) deaths occurred. The cumulative event rates for all-cause and cause-specific mortality were highest among participants in the TyG index quartile 4. In the multivariable Cox analysis, participants in the TyG index quartile 4 had significantly increased risks of all-cause, cardiovascular, and respiratory mortality compared with those in the quartile 1 (adjusted hazard ratio [HR] 1.21 (95% CI 1.17-1.24), 1.42 (1.29-1.56), and 1.68 (1.21-2.34), respectively). In contrast, the risk of cancer-related mortality was not increased in participants in the TyG index quartile 4. The risks of all-cause, cardiovascular, and respiratory mortality increased as the TyG index increased. However, there was no significant relationship between the TyG index and the risk of cancer-related mortality.

Conclusion: The TyG index can be a useful marker to identify young individuals at an increased risk of all-cause, cardiovascular, and respiratory mortality.

Context: Hereditary medullary thyroid carcinoma (MTC) is an inherited syndrome accounting for 25% of MTC cases. It is caused by germline RET mutations, which can be inherited or occur de novo.

Objective: This study aimed to define the prevalence and genetics of de novo MEN2 syndromes, which are not yet fully understood, and to characterize the parental origin of the RET de novo mutation.

Methods: We selected 152 of 215 families with hereditary MTC. In de novo cases, we sequenced the wild-type and mutated alleles of the index cases and compared their single nucleotide polymorphism profiles with those of their parents. Digital droplet PCR was performed to determine the presence of mosaicism in both the index case and the parents.

Results: In 24 of 152 (15.78%) families, the index case had a de novo mutation. Single nucleotide polymorphism analysis demonstrated that in all cases, the mutation occurred on the paternal allele. The absence of mosaicism supported the hypothesis that the mutation occurred during spermatogenesis. The mean age of fathers at the time of conception was, in some cases but not all, relatively advanced.

Conclusion: The prevalence of de novo hereditary MEN2 syndromes was approximately 16%, including MEN2B, and around 9% for other phenotypes. All de novo cases were of paternal origin and likely resulted from an acquired alteration in sperm DNA. The possible role of advanced paternal age in promoting de novo mutations could not be ruled out.

Context: Patients with familial partial lipodystrophy (FPLD) have increased risk of hepatic steatosis and its complications, for which there is no approved therapy.

Objective: This work aimed to investigate the efficacy and safety of obeticholic acid (OCA), a farnesoid X receptor agonist, for reducing hepatic steatosis in patients with FPLD.

Methods: A randomized, double-blind, placebo-controlled, crossover trial was conducted at an academic referral center. Ten women (age 19-60 years) with the Dunnigan variety of FPLD (FPLD2), harboring pathogenic heterozygous variants in the lamin A/C gene and hepatic steatosis (liver fat >5.6% by proton-density fat fraction mapping by magnetic resonance imaging), were included. Intervention included OCA 25 mg daily vs matched placebo for 4 months each with a 4-month washout period in between. The primary end point variable was liver fat. Secondary end point variables were serum triglycerides (TGs) and transaminase levels.

Results: All patients completed the trial. OCA therapy caused significant (39.6%) reduction in liver fat as compared to placebo (median liver fat [minimum-maximum]; 6.4% [2.4%-18.0%] vs 10.6% [3.4%-29.3%], respectively; P value for treatment × month interaction = .03). There were no significant differences in serum TGs or transaminase levels during OCA and placebo therapy. Overall, OCA was well tolerated except for itching in 4 patients compared to 2 on placebo. OCA, as compared to placebo, caused 24% increase in serum low-density lipoprotein cholesterol (mean 129 mg/dL vs 104 mg/dL, respectively; P = .0016).

Conclusion: OCA is safe and effective in lowering hepatic TG levels in patients with FPLD2.

Background: Risk alleles in lysine-specific demethylase 1 (LSD1) and striatin (STRN) are independently associated with greater salt-sensitive blood pressure (SSBP) and increased aldosterone and/or mineralocorticoid receptor (MR) activity. We tested the hypothesis that Black, but not White, risk allele carriers in both genes would have a more severe degree of SSBP than those carrying a single risk allele from either gene alone.

Methods: Individuals from the HyperPATH cohort were assessed for blood pressure and hormone levels after controlled low- and liberal-sodium diets. Black and White individuals with genotype data for LSD1 (rs587168) and STRN diplotype (rs888083 and rs6744560) were included.

Results: A total of 127 Black individuals were categorized: (1) higher risk: individuals who carried 1 or 2 risk alleles from both LSD1 and STRN and (2) lower risk: individuals who did not meet these criteria. In multivariable analysis, SSBP was higher among the higher risk vs the lower risk groups (18.9 ± 1.8 mm Hg vs 10.8 ± 1.6 mm Hg, P < .0001). Among hypertensive individuals, SSBP was 22.9 ± 2.5 mm Hg vs 12.9 ± 2.1 mm Hg for the higher risk vs lower risk groups, respectively (P < .0001). These results were confirmed in a second cohort of 37 Black individuals (P = .029). In 396 White individuals, no differences were observed.

Conclusion: Black, but not White, individuals with risk alleles from both LSD1 and STRN (44% of subjects) exhibited a higher degree of SSBP. In light of the MR-related drivers of SSBP in this population, MR blockade may be particularly effective.

Context: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is an inflammatory condition of the colon, characterized by watery diarrhea. Previous studies suggest an association between autoimmune thyroid diseases (AITDs) (Hashimoto thyroiditis and Graves disease) and MC; however, large-scale histology studies are lacking.

Objective: To assess the association between AITDs and future onset of MC.

Methods: We conducted a nationwide, matched case-control study. Patients with biopsy-confirmed MC diagnosed between 2006 and 2017 were identified through the population-based histopathology cohort ESPRESSO. Data on AITDs and covariates were retrieved from Swedish national health care registers. Odds ratios (ORs) for MC associated with prior AITDs were estimated using conditional logistic regression. Sibling comparisons were performed to minimize shared genetic and environmental confounding.

Results: Among 10 301 MC cases and 48 712 controls, AITDs were significantly more prevalent in MC patients (12.0%) than in controls (7.8%), yielding an adjusted OR of 1.65 (95% CI 1.54-1.77). This association was attenuated but remained significant in sibling analyses (OR 1.26; 95% CI 1.11-1.43) The association was stronger in patients diagnosed with MC before age 50 (OR 2.41; 95% CI 2.02-2.89). Subgroup analyses revealed no difference between CC and LC or between sexes.

Conclusion: Individuals with AITDs are at an increased risk of developing MC. That this association was robust across various subgroups may be indicative of shared underlying mechanisms. Our findings highlight the importance of being vigilant of gastrointestinal symptoms in patients with AITDs and that patients with persistent symptoms despite achieving euthyroidism should be evaluated for MC.

Context: Patients affected by the classic form of congenital adrenal hyperplasia (CAH) need lifelong glucocorticoid (GC) therapy. GC represents one of the primary causes of secondary osteoporosis; however, the effect of steroid therapy on bone mineral density (BMD) in patients with CAH is still controversial.

Objective: To evaluate and compare the BMD of a group of prepubertal patients and a subgroup of young adult patients with CAH receiving chronic GC therapy, with healthy controls.

Design: Retrospective observational study.

Setting: A referral center for pediatric endocrinology.

Patients and healthy controls: Fifty-six prepubertal children with CAH treated with GC from diagnosis and 60 prepubertal healthy children of comparable age. A subgroup of 36 young patients was studied after the completion of puberty, and their BMD was compared to that of 51 young adult healthy volunteers.

Methods: BMD was measured in the lumbar spine and in the whole body by dual-energy x-ray absorptiometry. Multivariate models were used for the comparison of BMD measurements between patients and control subjects.

Results: Whole-body BMD measurements of patients were significantly lower compared with healthy controls, both in boys and in girls. No differences were found in lumbar spine measurements. BMD expressed as Z-score decreased markedly in CAH patients from prepuberty to adulthood, particularly in young adult males. Men with CAH showed lumbar spine BMD values significantly lower than control subjects.

Conclusion: Boys and young adult men with classic form of CAH have lower BMD values compared with healthy controls. This may put them at risk of developing osteoporosis early in life.

Context: Establishing the genetic basis of early-onset primary ovarian insufficiency (EO-POI, <25 years) is important, but defining variant pathogenicity is challenging.

Objective: We aimed to elucidate the genetic architecture of EO-POI in a unique, large cohort. Young women with EO-POI (n = 149; n = 31 familial, n = 118 sporadic) attending a specialist reproductive unit were included. Exome sequencing was performed. After filtering, variants were retained that were: (1) rare/novel (minor allele frequency <0.01%); (2) predicted pathogenic/likely pathogenic; and (3) enriched in the cohort. Each variant was assigned to a category: Category 1, variants in Genomics England Primary Ovarian Insufficiency PanelApp genes (n = 69); Category 2, variants in other POI-associated genes (n = 355) or Category 1 variants following unexpected inheritance patterns; and Category 3, homozygous variants in novel candidate POI genes.

Results: A total of 127 Category 1 or 2 variants were identified in 74 different genes (heterozygous 30.9%; homozygous 9.4%; polygenic 21.8%). In familial EO-POI, 64.7% (11/17 kindred) had a Category 1 or 2 variant identified (homozygous: STAG3, MCM9, PSMC3IP, YTHDC2, ZSWIM7; heterozygous: POLR2C, NLRP11, IGSF10, PRKD1, PLEC; polygenic: PDE3A, POLR2H, MSH6, CLPP). In sporadic EO-POI, 63.6% (n = 75/118) women had a variant identified: 21.2% (n = 25) Category 1; 42.4% (n = 50) Category 2. Novel POI candidate genes (Category 3) included PCIF1, DND1, MEF2A, MMS22L, RXFP3, C4orf33, and ARRB1.

Conclusion: The genetic basis of EO-POI is complex and affected genes span ovarian developmental processes from fetal life to adulthood. Establishing the pathogenicity of individual heterozygous variants can be challenging. However, some women have clear monogenic causes, particularly in familial POI with autosomal recessive inheritance. Others have potential polygenic causes. We describe novel candidate POI genes warranting further exploration.