Upper Range Of Normal Research Articles

Associations between serum sodium level ranges with geriatric syndromes.

To determine prevalences of common geriatric syndromes in the setting of different normal ranges of serum sodium. In this cross-sectional study, 2048 older adults (aged ≥ 60) who underwent comprehesive geriatric assessment between 2016 and 2023 in one geriatric outpatient clinic were evaluated. Patient groups included moderate hyponatremia (< 130mEq/L, n = 28, 1.6%), mild hyponatremia (130-134mEq/L, n = 130, 7.3%), lower-normal range (135-140mEq/L, n = 904, 50.4%), upper normal range (141-145mEq/L, n = 702, 39.2%), and hypernatremia (> 145mEq/L, n = 29, 1.6%). A separate analysis was also performed according to the following classification: borderline hyponatremia (133-137mEq/L), normal (138-142mEq/L), and borderline hypernatremia (143-147mEq/L). Logistic regression analysis was performed to determine associations between serum sodium groups and geriatric syndromes. After applying the inclusion/ exclusion criteria a total of 1792 patients were included, with a mean age of 81 ± 8years and 71% were female. With the exception of geriatric depression, all other syndromes were more prevalent in the lower-normal range than the upper normal range. After adjustments for age, sex, comorbidities, functional status, and drug exposures, upper normal range of serum sodium was associated with lower risks of dependency (OR 0.72, 95% CI 0.53-0.99, p = 0.043) and malnutrition (OR 0.69, 95% CI 0.51-0.94, p = 0.018). Compared to borderline hyponatremia, borderline hypernatremia was associated with lower risks of polypharmacy (OR 0.58, 95% CI 0.37-0.89, p = 0.014), dependency based on basic activities of daily living (OR 0.55, 95% CI 0.31-0.98, p = 0.042), malnutrition (OR 0.55 95% CI 0.33-0.91, p = 0.020), and frailty (OR 0.65, 95% CI 0.44-0.96, p = 0.031). Compared to a lower normal level of sodium, an upper normal level of sodium was associated with a lower risks of dependency and malnutrition. Borderline hypernatremia was associated with lower prevalences of polypharmacy, dependency, frailty, and malnutrition compared to borderline hyponatremia among geriatric outpatients in this single-center study.

Association Between Body Mass Index and Risk of Aortic Stenosis in Women in the Swedish Medical Birth Registry.

Overweight and obesity are increasing globally with aging, as are life expectancy and aging-associated disorders, including calcific aortic stenosis (AS). Studies investigating the correlation between high body mass index (BMI) and AS are contradictory and inconclusive. This study examines a potential association between BMI and AS in women. By linking the Swedish Medical Birth Register and the Swedish National Patient Register, we included women aged 18 to 55 years with a first childbirth from 1981 to 2020. Diagnosis of AS and comorbidities were defined according to the International Classification of Diseases (ICD) codes. The women were divided into groups on the basis of BMI. Cox proportional hazards regression models were used to investigate the difference in the risk of being diagnosed with AS, with reference BMI 20 to <22.5 kg/m2. Among the 1 722 625 included women, the mean age was 28 years, and mean BMI was 24 kg/m2, with 21% being overweight (BMI 25 to <30 kg/m2) and 8.5% obese (BMI ≥30 kg/m2). During median follow-up of 19.5 years, 2488 women (0.14%) were diagnosed with AS. The age-adjusted risk of being diagnosed with AS increased with higher BMI to 2.82 (95% CI, 2.44-3.25) times higher in women with BMI 30 to <35 kg/m2, and to 3.72 (95% CI, 2.95-4.70) times higher in those with BMI ≥35 kg/m2. Similar results were found after excluding AS of rheumatic pathogenesis. An increase in BMI from its upper normal range was consistently and independently associated with the risk of developing AS in women.

6998 Giant Pheochromocytoma: A Retrospective Single-Center Study

Abstract Disclosure: B. Bahrani Fard: None. N. Nikravangolsefid: None. J. Maroun: None. A. Cross: None. T. Foster: None. T. McKenzie: None. W. Young Jr: None. B.M. Dy: None. M. Lyden: None. I. Bancos: None. Background: Giant pheochromocytomas (PHEO), defined based on size &amp;gt; 10 cm, are rare. Data on clinical presentation, management, and prognosis of giant PHEOs are scarce. Objectives: to determine prevalence of giant PHEO and compare presentation, management, and outcomes of patients with giant vs non-giant PHEOs. Methods: We conducted a single-center retrospective cohort study of consecutive patients with giant PHEO and randomly chosen patients with non-giant PHEO (referents) at 6:1 ratio, evaluated between 2000-2023. All variables were extracted from the electronic medical record. Results: Of 828 patients with PHEO evaluated between 2000 and 2023, 31 (3.7%) had giant PHEO (median size 12 cm, IQR 10.0-13.5). In comparison to referents (n=186, median size 4 cm, IQR, 2.9-5.0), patients with giant PHEO were similar in age (median age 53 vs 55 years, P=.55), more frequently discovered based on symptoms (52% vs 32%, P=.04), and less likely to be bilateral (3% vs 12%, P=.31). Genetic testing was performed in 103 (48%) of patients, without group differences, however, patients with giant PHEO were less likely to have an associated germline mutation detected (7% vs 47%, P=.004). Patients with giant PHEO had more symptoms of catecholamine excess (median of 2 vs 1, P=.04) and presented with a higher prevalence of severe metanephrine excess &amp;gt;10 times above upper normal range (76% vs 30%, P&amp;lt;.0001). Adrenalectomy was performed in 94% of patients with giant PHEOs and in 100% referents, with higher rates of open adrenalectomy in giant PHEO (86% vs 14%, P&amp;lt;.0001). In addition to preoperative alpha-adrenergic blockade (89%), metyrosine was used in 14 (7%) patients, mostly in patients with giant PHEO (26% vs 3%, P&amp;lt;.0001). Patients with giant PHEO had a longer hospital length of stay (laparoscopic: median 5 vs 2 days, P&amp;lt;.0001; open: median 6 vs 5 days, P=.24), and a higher complication rate (31% vs 10%, P=.006).Median follow up was 3 years (IQR 1-8) years, similar in patients and referents. Metastases developed at a much higher rate in patients with giant PHEOs (45% vs 4% in referents, P&amp;lt;.0001). Disease specific mortality was 7% in patients with giant PHEOs and 0% in referents. Conclusion: Patients with giant PHEO were more symptomatic, had a higher degree of catecholamine excess, and a higher rate of perioperative complications. Almost half of patients with giant PHEO developed metastases, warranting a close follow-up. Presentation: 6/2/2024

IGF1 Haploinsufficiency: Phenotype and Response to Growth Hormone Treatment in 9 Patients.

The clinical features of bi-allelic IGF1 defects are well established, i.e., severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness. However, information on clinical and endocrine consequences of heterozygous IGF1 variants and treatment options is scarce. We aimed at extending the knowledge base of the clinical presentation and growth response to recombinant human growth hormone (rhGH) of patients carrying such variants. Retrospective case series of patients with pathogenic heterozygous IGF1 variants. Nine patients from six families were included, harbouring five whole or partial gene deletions and one frameshift variant resulting in a premature stop codon (three de novo, one unknown inheritance). In the other two families, variants segregated with short stature. Mean (SD) birth length was -1.9 (1.3) SDS (n = 7), height -3.8 (0.6) SDS, head circumference -2.5 (0.6) SDS, serum IGF-I -1.9 (0.7) SDS, serum IGFBP-3 1.1 (0.4) SDS (n = 7), and GH peak range 5-31 μg/L (n = 4). Five patients showed feeding problems in infancy. Average height increased after 1 and 2 years of rhGH treatment by 0.8 SDS (range 0.3-1.3 SDS) and 1.3 SDS (range 0.5-2.0 SDS), respectively. Adult height in 2 patients was -2.8 and -1.3 SDS, which was, respectively, 1.3 and 2.9 SDS taller than predicted before start of treatment. Haploinsufficiency of IGF1 causes a variable phenotype of prenatal and postnatal growth failure, microcephaly, feeding difficulties, low/low-normal serum IGF-I values in contrast to serum IGFBP-3 in the upper-normal range. Treatment with rhGH increased growth in the first 2 years of treatment, and in 2 patients adult height after treatment was higher than predicted at treatment initiation.

Fasting Triglycerides in the Upper Normal Range Are Independently Associated with an Increased Risk of Diabetes Mortality in a Large Representative US Population.

The association between normal-range triglyceride levels and diabetes mortality remains unclear. This cohort study aimed to elucidate this relationship by examining 19,010 US adult participants with fasting serum triglycerides below 150 mg/dL. Cox proportional hazards models were employed to estimate mortality hazard ratios (HRs) and 95% confidence intervals (CIs). Participants were followed up for a mean of 15.3 years, during which 342 diabetes deaths were recorded. A 1 natural log unit increase in triglycerides was associated with a 57% higher risk of diabetes mortality (adjusted HR, 1.57; 95% CI, 1.04-2.38). Comparable results were obtained when triglycerides were analyzed in quartiles. Receiver operating characteristic curve analysis identified an optimal triglyceride cutoff of 94.5 mg/dL for diabetes mortality; individuals with triglyceride levels above this threshold faced a greater risk of diabetes mortality (adjusted HR, 1.43; 95% CI, 1.12-1.83). Further investigation revealed a positive association between normal triglyceride levels and all-cause mortality, though no association was observed between normal triglycerides and mortality from hypertension or cardiovascular disease. In conclusion, elevated triglyceride levels within the normal range were associated with an increased risk of diabetes mortality. Individuals with triglyceride levels of 95 mg/dL or higher may require vigilant monitoring for diabetes and its associated complications.

Head circumferences measured during developmental monitoring visits before diagnosis of childhood-onset craniopharyngioma.

Craniopharyngiomas (CP) are histologically benign (WHO grade 1), embryonal malformations which are related to remnants of the Rathke's pouch and are located in the (peri)sellar region. Already before CP diagnosis, many patients show a reduced growth velocity and tend to present with weight gain. However, it is unknown whether patients with CP develop an increased head circumference (HC) before CP diagnosis, which could be a useful early diagnostic indicator. For a cohort of 83 patients recruited in the multicenter studies KRANIOPHARYNGEOM 2000 and HIT-ENDO data on HC could be analyzed, based on medical records assessed in developmental monitoring visits performed at defined time points before CP diagnosis. When comparing HC standard deviation scores (SDS) before CP diagnosis in 83 patients at defined time points between birth and 4 years of age, all HC were in the upper normal range. However, CP patients diagnosed at an age ≤4 years with initial hypothalamic involvement presented with a tendency towards an increased HC SDS early before CP diagnosis at routine medical examinations during the first 7 months of life. We conclude that monitoring of growth and weight development including HC can lead to early CP diagnosis and treatment. This might prevent higher grades of hypothalamic involvement and lead to an improvement of quality of life after CP. Further studies on the specific value of HC as a diagnostic marker are warranted.

Blood pressure responses to testosterone therapy are amplified by hematocrit levels in opioid-induced androgen deficiency: a double-blind, randomized, placebo-controlled trial.

Our study aimed to examine the effect of testosterone replacement therapy (TRT) on blood pressure in opioid-treated men with relative hypogonadism, and whether the effect of TRT on blood pressure was modified by body composition, red blood cell levels, or carotid intima media thickness. Men (over 18 years old) receiving opioid treatment and total testosterone less than 12 nmol were randomly assigned to receive either TRT or placebo. Baseline and 6-month measurements included anthropometric measurements, office blood pressure (OBPM), 24-h ambulatory blood pressure, blood samples, and carotid ultrasound. The mean systolic OBPM increased by 6.2 mmHg (0.2-12.1) in the TRT group and decreased by 7.0 mmHg (1.0-15.1) in the placebo group, with a mean difference of 13.2 mmHg (3.4-23.1), P = 0.01. In the TRT group, a 10 mmHg increase in systolic OBPM was associated with an increase in hematocrit of 0.3% points (0.1-0.5) ( P = 0.01), whereas no association was observed in the placebo group ( P = 0.266). Daytime SBP showed a nonsignificant increase of 5.2 mmHg (-1.7, 12.1) ( P = 0.134) in the TRT group compared to that in the placebo group. However, the impact of TRT on the increase in daytime ambulatory blood pressure was significantly accentuated by baseline values of BMI, hematocrit, and hemoglobin. In conclusion, TRT was associated with higher OBPM compared to placebo, and the increase in blood pressure was linked to higher hematocrit during TRT. Our data suggest that men with opioid-induced androgen deficiency, particularly those with obesity or red blood cell levels in the upper normal range, are more susceptible to increased daytime SBP during TRT.

Trends in the prevalence rates and predictive factors of coeliac disease: A long-term nationwide follow-up study.

The prevalence of coeliac disease doubled in Finland from 1980 to 2000. To investigate whether this increase is continuing and if there are specific patient-related factors predicting the development of coeliac disease at a population level. We elicited comprehensive health data in the nationwide Health 2000 and Health 2011 surveys. Serum samples were taken for the measurement of tissue transglutaminase antibodies (TGA); subjects who were seropositive were tested for endomysial antibodies (EmA). Coeliac disease was defined either as a reported diagnosis or as positive TGA and EmA. The surveys comprised, respectively, 6379 and 4056 individuals, forming representative samples for 2,946,057 and 2,079,438 Finnish adults. Altogether 3254 individuals participating in both surveys comprised a prospective follow-up cohort. Prevalence of coeliac disease was 2.12% in 2000 and 2.40% in 2011 (p = 0.156). In the prospective cohort, 16 out of the 3254 (0.49%) subjects developed coeliac disease during follow-up from 2000 to 2011, with an annual incidence rate of 45 per 100,000 persons. Positive TGA without EmA (OR: 133, 95% CI: 30.3-584), TGA values in the upper normal range (51.1, 16.0-163), and after adjusting for TGA, previous autoimmune co-morbidity (8.39, 4.98-35.9) in 2000 increased the likelihood of subsequent coeliac disease. The nationwide prevalence of coeliac disease kept on rising from 2.12% in 2000 to 2.40% in 2011 in Finland. Positive TGA without EmA, TGA titres in the upper normal range and a pre-existing autoimmune disease predisposed to coeliac disease during the 10-year follow-up.

Abstract 12088: Left Ventricular Non-Compaction, Coronary Artery Fistula, and Infective Endocarditis: A Rare Combination

Description of Case: A 48-year-old man underwent echocardiography for multifocal subacute infarctions found on brain MRI. No intracardiac shunts were found, but prominent LV trabeculae raised suspicion of LV non-compaction (LVNC). LV ejection fraction was 53%, and LV volume was within upper-normal range. Cardiac MRI confirmed these findings, although non-compacted:compacted myocardium ratio was 1.9. (Panel A-B) A right coronary artery to LV fistula was also diagnosed. (Panel C-D) The patient was followed-up uneventfully, but 10 months later was admitted after a generalized seizure episode. Brain MRI detected multiple new hemorrhagic infarcts, and echocardiography revealed a 10.8mmх10.1mm mobile mass and high-speed diastolic flow near the basolateral LV wall. (Panel E-F) Gemella morbillorum was identified on two blood cultures. The patient underwent surgery for fistula closure and vegetation resection. Vegetation pathology and culture however was negative for bacterial growth. Paroxysmal atrial fibrillation was also detected, before discharge with full recovery. Discussion: LVNC and coronary artery fistula (CAF) are both caused by arrest in embryonic myocardial compaction. Despite a hypothetical common origin, reports of co-occurrence are extremely rare. This is the first to report the association of a mild form of LVNC and a single large CAF. This is also the first to report infective endocarditis due to CAF by G. morbillorum . G. morbillorum infective endocarditis is rare, subacute in course, and causes significant destruction. The extensive, prolonged embolism found here has not been reported in other cases of CAF-associated infective endocarditis and may be due to G. morbillorum .

THU221 Measurements Of Head Circumference During Developmental Monitoring Visits Before Diagnosis Of Pediatric Craniopharyngioma

Abstract Disclosure: J. Beckhaus: None. S. Boekhoff: None. L. Krieger: None. J. Peng: None. C. Friedrich: None. H.L. Muller: None. Craniopharyngiomas (CP) are congenital, benign, embryonic malformations which arise from ectoblastic remnants of Rathke’s pouch and are located in the (supra-)sellar region. Many patients show a reduced growth rate and an increased BMI early before the diagnosis of CP. However, it is unknown whether patients with CP present with increased head circumference before diagnosis. A cohort of 83 patients was screened for medical records of their developmental monitoring visits. We observed, that CP patients with hypothalamic involvement of their tumor tend to have an increased head circumference SDS before CP diagnosis. When comparing head circumference SDS before diagnosis at defined time points between birth and four years of age, all head circumferences were in the upper normal range. However, no statistically noticeable differences were found between hypothalamic involvement and no hypothalamic involvement of the tumor. Congenital embryonic malformations such as CP located in the parasellar area can have impact on cerebrospinal fluid circulation and lead higher head circumferences due to hydrocephalus early before diagnosis. Our results show, that head circumference SDS could be an effective early-indicator for CP. A standardized procedure for head circumference measurements during developmental monitoring visits should be implemented in clinical care. We anticipate that our study is the starting point for prospective studies with larger sample size to assess the potential predictive value of head circumference measurements for an early CP diagnosis. Presentation: Thursday, June 15, 2023

Determinants of hyperphosphatemia and its relation with hemoglobin levels among hemodialysis patients in two hospitals from Syria: a prospective cross-sectional study.

A prospective cross-sectional study was conducted among 146 HD patients from two HD centers in Syria, between June 2021 and March 2022. All patients at least 18 years old on maintenance HD were enrolled. The threshold of phosphorus (phos) level was divided by the upper normal range among HD patients (5.5mg/dl). We used parametric and nonparametric statistics, the Pearson and Spearman correlations with simple and multiple linear regressions between study variables. 36.9% of patients had a serum phos level of 5.5 or less (norm phos group), and 63.1% of patients had a serum phos level higher than 5.5 (high phos group). Also, 60.9% of patients had hemoglobin (Hb) less than 10g/dl, and 40.4% of patients had Hb at least 10g/dl. Age, type of HD access, phos binders (P-binders), parathyroid hormone (PTH), and calcium (Ca) showed significant effects on phos levels. Most patients were using arteriovenous fistula (AVF) (89.7%) as a HD access, and the meantime on HD was higher in the norm phos group compared to the high phos group. In a multivariate and univariate logistic regression analysis, hyperphosphatemia increased with increasing urea (Ur) and creatinine (Cr) levels, while the odds declined with increasing time on HD. Hb did not show a significant relation with phos by using several statistical methods. A high prevalence of hyperphosphatemia and anemia was encountered among this sample of HD patients from Syria. There was no correlation between phos and Hb levels in contrast to previous conflicting studies, which mandates future studies to evaluate this correlation and further efforts to determine the range of phos that could have a benefit on anemia with respect to other comorbidities.

Increased Serum Sodium at Acute Kidney Injury Onset Predicts In-Hospital Death.

Over the last decades, acute kidney injury (AKI) has been identified as a potentially fatal diagnosis which substantially increases in-hospital mortality in the short term and morbidity/mortality in the long term. However, reliable biomarkers for predicting AKI-associated outcomes are still missing. In this study, we assessed whether serum sodium, measured at different time points during the in-hospital treatment period, provided prognostic information in AKI. This was a retrospective, observational cohort study. AKI subjects were identified via the in-hospital AKI alert system. Serum sodium and potassium levels were documented at five pre-defined time points: hospital admission, AKI onset, minimum estimated glomerular filtration rate, minimum and maximum of the respective electrolyte during the treatment period. In-hospital death, the need for kidney replacement therapy (KRT) and recovery of kidney function were defined as endpoints. Patients who suffered in-hospital death (n = 37, 23.1%) showed significantly higher serum sodium levels at diagnosis of AKI (survivors: 145.7 ± 2.13 vs. non-survivors: 138.8 ± 0.636 mmol/L, P = 0.003). A logistic regression model was significant for serum sodium levels in patients with in-hospital death (X2, P = 0.003; odds ratio = 1.08 (1.022 - 1.141); R2 = 0.082; d = 0.089). This suggests an increase of the relative risk for in-hospital death by 8% with every unit of serum sodium increase. Patients with a sodium above the upper normal range at AKI diagnosis were also more likely to suffer in-hospital death (P = 0.001). In summary, we present evidence that serum sodium, measured at time of AKI diagnosis, potentially serves as a predictor for in-hospital death in patients with AKI.

A Project work on Recent approches in the Treatment of Diabetic Nepheropathy

Renal failure is a common long-torm complication of diabetes mellitus. Stages of diabetic nephropathy have been described that characterize its clinical course. Diabetic nephropathy develops secondary to long- changes that damage the glomeruli’s. Therapy that focuses on the control of glomerular pressures and systemic hypertension can slow the progression of proteinuria and deterioration of renal function. Angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers have been demonstrated to be effective in the management of diabetic nephropathy. A systematic approach to the patient with diabetes with help identify those individuals early in the course of disease when proper therapy may be most helpful. Diabetic nephropathy is the leading cause of chronic renal disease and a major cause of cardiovascular mortality. Diabetic nephropathy has been categorized into stages: micro albuminuria and macro albuminuria. The cut-off values of micro- and macro albuminuria are arbitrary and their values have been questioned. Subjects in the upper-normal range of albuminuria seem to be at high risk of progression to micro- or macro albuminuria and they also had a higher blood pressure than normoalbuminuric subjects in the lower norm albuminuria range. Diabetic nephropathy screening is made by measuring albumin in spot urine. If abnormal, it should be confirmed in two out three samples collected in a three to six-months interval. Additionally, it is recommended that glomerular filtration rate be routinely estimated for appropriate screening of nephropathy, because some patients present a decreased glomerular filtration rate when urine albumin values are in the normal range. The two main risk factors for diabetic nephropathy are hyperglycemia and arterial hypertension, but the genetic susceptibility in both type 1 and type 2 diabetes is of great importance. Other risk factors are smoking, dyslipidemia, proteinuria, glomerular hyper filtration and dietary factors. Nephropathy is pathologically characterized in individuals with type 1 diabetes by thickening of glomerular and tubular basal membranes, with progressive meningeal expansion (diffuse or nodular) leading to progressive reduction of glomerular filtration surface. Concurrent interstitial morphological alterations and hyalinization of afferent and efferent glomerular arterioles also occur. Podocytes abnormalities also appear to be involved in the glomerulosclerosis process. In patients with type 2 diabetes, renal lesions are heterogeneous and more complex than in individuals with type 1 diabetes. Treatment of diabetic nephropathy is based on a multiple risk factor approach, and the goal is retarding the development or progression of the disease and to decrease the subject's increased risk of cardiovascular disease. Achieving the best metabolic control, treating hypertension (&lt;130/80 mmHg) and dyslipidemia (LDL cholesterol &lt;100 mg/dl), using drugs that block the renin-angiotensin-aldosterone system, are effective strategies for preventing the development of micro albuminuria, delaying the progression to more advanced stages of nephropathy and reducing cardiovascular mortality in patients with diabetes.

Relationship between thyroid hormone levels in euthyroid patients before HSCT and time to achieve neutrophil and platelet engraftment: an analytical cross-sectional study

Introduction. The time to reach neutrophil (NE) and platelet engraftment (PE) in hematopoietic stem cell transplantation (HSCT) is one of the most important factors indicating transplantation survival. The aim of this study was to investigate the relationship between thyroid hormone levels before HSCT and the time to achieve NE and PE. Material and methods. The relationship between thyroid hormone levels before HSCT, age, gender, type of HSCT, type of disease and cluster of differentiation 34+ (CD34+) cell count and the number of days to reach NE and PE was examined in 37 clinically and laboratorially euthyroid patients. Results. An odds ratio (OR) of &gt; 6 was observed in the probability of time to NE &gt; 10 days in patients with thyroid-stimulating hormone (TSH) &gt; 2.89 mU/L in the upper normal range (UNR) and male patients, also in the probability of time to PE &gt; 15 days in patients with TSH &gt; 2.89 mU/L in the UNR. Statistically significant p -value and confidence interval were found in the probability of time to NE &gt; 10 days in male patients (OR = 8.58, p -value = 0.036) and time to PE &gt; 15 days in patients with TSH &gt; 2.89 mU/L in the UNR (OR = 14.32, p -value = 0.041). Conclusions. Treatment with low dose levothyroxine can be cautiously recommended to achieve TSH to ≤2.8 mU/L in the lower normal range before performing HSCT in euthyroid patients, which will reduce the times to NE and PE and help earlier discharge of patients.

RF13 | PMON59 Tracking and Cumulative Lifetime Exposure to Circulating IGF-I in 6,459 Healthy Individuals and in SGA Children Treated with GH

Abstract Background: /objective Insulin-like-growth-factor-I (IGF-I) levels in the lower or upper normal range have been proposed as a biomarker of risk for later disease in healthy adults, specifically cardiovascular disease and cancer. In addition, concern has been raised about the frequently observed supraphysiological IGF-I levels in non-growth-hormone-deficient children treated with growth hormone (GH). However, whether a single IGF-I measurement is a valid indicator of cumulative lifetime exposure to IGF-I and thus disease risk is not established. We aimed to evaluate intra-individual longitudinal tracking of IGF-I and IGF-binding-protein-3 (IGFBP-3) levels and to estimate cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. We hypothesized that individuals follow a certain IGF-I trajectory throughout life and that GH therapy in childhood does not increase lifetime IGF-I exposure substantially. Methods We performed a combined cross-sectional (n=5,326) and longitudinal (n=1,133) study of 6,459 healthy participants (49% male) aged 0­­­–76 years recruited as part of six Danish population-based studies, resulting in a total of 9,963 serum samples. In addition, we included 238 samples from nine short children born small-for-gestational-age (SGA) before, during and after GH treatment. Serum samples were analyzed for IGF-I and IGFBP-3 with the IDS-iSYS immunoassay and anthropometric measures were obtained. Intra-individual tracking was determined by intraclass correlation coefficients (ICC) derived from a linear mixed model with IGF-I (SDS) or IGFBP-3 (SDS) as dependent variable and subject as random effect, unadjusted and adjusted for BMI-changes. Cumulative lifetime exposure to IGF-I was estimated by calculating area under the curve of the predicted SD trajectory from 0-76 years. Results Sex- and age-specific reference curves for IGF-I and IGFBP-3 were established. For IGF-I, ICCs were 0.50 (95% CI: 0.47–0.53) and 0.53 (0.50–0.56) for male and female participants, respectively. ICCs for IGFBP-3 were 0.52 (0.49–0.55) for male participants and 0.59 (0.56–0.62) for female. Cumulative lifetime IGF-I exposure was significantly higher in female (mean ± SD, 12,723 ± 3,691) than in male participants (12,563 ± 3,393); p=0.02. The SGA patients had a mean (range) GH-treatment duration of 9.2 years (5.2–11.9). Treatment caused an increase in estimated cumulative lifetime IGF-I exposure of 1,759 ± 556 shifting them from a mean estimated lifetime exposure without treatment of 9,512 ± 1,889 to 11,271 ± 1,689 with treatment. This corresponded to a rise in IGF-I trajectory (SDS) of 0.55 SD ± 0.18, from -0.89 SD ± 0.57 to -0.35 SD ± 0.49. Conclusion Our results suggest that IGF-I and IGFBP-3 levels are tracking throughout life and that a single measurement reliably reflects lifetime exposure. We, for the first time, estimated lifetime exposure to IGF-I in healthy individuals and show that pediatric GH therapy only slightly increases lifetime exposure and not beyond levels commonly found in the reference population. Presentation: Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Change of renal function after short-term use of cardioprotective agents in patients with type 2 diabetes is not accurately assessed by the change of estimated glomerular filtration rate: an observational study

BackgroundAfter initiating cardioprotective agents, a fall of estimated glomerular filtration rate (eGFR) has been reported in several studies. Our goal was to evaluate the accuracy of change of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR in patients with type 2 diabetes (T2D) after short-term pharmacological intervention with angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, gliptin or sodium-glucose cotransporter-2 inhibitor.MethodsWe analyzed 190 patients with T2D in the early stage of the disease, having no overt renal impairment by CKD-EPI equation. In each patient, we measured GFR (mGFR) by applying the constant infusion input clearance technique with sinistrin (Inutest; Fresenius, Linz, Austria) at baseline and after short-term (4–12 weeks) pharmacological intervention with cardioprotective agents (ramipril, telmisartan, linagliptin, metformin, empagliflozin) that potentially lead to an alteration of renal function. Simultaneously, a standardized analysis of serum creatinine was performed and eGFR was estimated by the CKD-EPI equation.ResultsAverage mGFR was 111 ± 20 ml/min/1.73m2, whereas eGFR was lower with 93 ± 13 ml/min/1.73m2. The ratio eGFR/mGFR in relation to mGFR was almost curvilinear, showing an underestimation of renal function by eGFR in the upper normal range. At baseline only 80 patients (42%) lay within ± 10% of mGFR and the concordance correlation coefficient (CCC) was extremely low (− 0.07). After short-term pharmacological intervention changes in eGFR and mGFR correlated with each other (r = 0.286, p < 0.001). For example, for a given mGFR of 111 ml/min/1.73m2, a change of mGFR by ± 10% corresponded to ± 11 ml/min/1.73m2, but the confidence interval of eGFR was 25 ml/min/1.73m2. The CCC was low (0.22).ConclusionThe agreement between eGFR by CKD-EPI and mGFR is modest and the change of renal function after short-term pharmacological intervention is not accurately and precisely reflected by the change of eGFR in patients with T2D in the early stage of their disease.

EXTREMELY HIGH DIRECT PLASMA RENIN IN A YOUNG WOMAN WITH NEGATIVE IMAGING FOR RENOVASCULAR HYPERTENSION

Objective: Direct plasma renin (DPR) has a much broader distribution than plasma renin activity (PRA). The finding in one patient of extremely high DPR values without apparent cause led us to the diagnosis and successful treatment of renovascular hypertension which had been initially ruled out by magnetic resonance angiography. Design and method: Review of the patient’s clinical records and the relevant literature. Results: A 39-year-old woman, long-term user of oral contraceptives was referred to our Hypertension Clinic. For the last two years she had presented severe hypertension, with BP often &gt; 200/120 mmHg, poorly responding to antihypertensive drugs including ACEI or ARB plus calcium antagonists, diuretics, spironolactone, doxazosin and bisoprolol. She reported frequent holocranial non-pulsatile headaches without pallor, tachycardia, nausea or other vegetative symptoms. Laboratory testing was normal except for albuminuria (378 mg/g Cr) with normal plasma creatinine,eGFR, potassium, TSH and ACTH. Blood pressure remained high after contraceptive withdrawal. Physical examination showed only grade I overweight. ABPM showed diurnal 198/96 mmHg and nocturnal 186/89 mmHg, non-dipper without marked highs or lows. Echocardiography showed moderate LVH but ruled out heart failure. All drugs except diltiazem and doxazosin were withdrawn for a month, plasma metanephrines and cortisol suppression were normal, and plasma aldosterone was in the upper normal range (29.6 ng/dL) while DPR was extremely high (2196 mU/L, normal upper limit 39 mU/L). Renovascular hypertension (or reninoma) was suspected, but magnetic resonance renal angiography was informed as normal. However, the left kidney was significantly smaller and hypoperfused. A standard renal angiogram showed fibromuscular dysplasia with severe left stenosis. Angioplasty was performed, and after 3 months the patient’s blood pressure is well controlled with 120 mg slow-release diltiazem daily, and her plasma angiotensin and renin are normal. Conclusions: DPR can be raised by low-salt diet, hypovolemia, drugs such as diuretics, ACEIs and ARBs, hyperthyroidism, pheochromocytoma/paraganglioma and edematous states (heart or liver failure, nephrotic syndrome). However these conditions are unlikely to cause extremely high renin. Renovascular hypertension or reninoma should be suspected, even when the initial imaging seems negative. Fibromuscular dysplasia is likelier than atherosclerotic stenosis or reninoma in contraceptive users.

Increased serum pro-B-type natriuretic peptide in hematopoietic progenitor cell donors stimulated with G-CSF.

Hematopoietic stem cells (HPCs) donors mobilized by granulocyte-colony-stimulating factor (G-CSF) can develop various signs and symptoms. proBNP (pro-B-type natriuretic peptide) is a serum marker of heart failure. A donor who developed severe adverse reactions after G-CSF mobilization was found to have high serum proBNP levels. We followed additional donors who received identical mobilization regimen to investigate the prevalence of this phenomenon. Eighteen healthy donors underwent a mobilization regimen of 10μg/Kg G-CSF daily for 5 days prior to allogeneic HPC collection using Spectra Optia between January 2016 and February 2017 were included in this study. Serum proBNP levels were measured before and after G-CSF stimulation and immediately after apheresis. Apheresis collection parameters and other laboratory results were also reviewed. The majority of donors (86.7%) had post-G-CSF elevation of serum proBNP. Seven of those had elevated proBNP above upper normal range (124 pg/ml). The subgroup of donors with normal proBNP is younger (median age of 37 vs 42 years), with majority being male (90.9% vs 28.6%) and with smaller processed blood volume (2.2 vs 3 × total blood volume). This case series demonstrates an increase of serum proBNP can be common in HPC donors stimulated with 5 days of 10 mcg/kg G-CSF. This is an adverse reaction that has not been described before. The temporary elevation of proBNP in these donors is not associated with ventricular dysfunction of the heart. The risk factors for marked elevation of proBNP post-G-CSF should be further investigated.

Risk Factors for Hepatotoxicity Due to Paracetamol Overdose in Adults.

Background and Objectives: Over-the-counter availability and a good safety profile make paracetamol one of the most common analgesics in developed countries but also the leading cause of liver failure due to overdose. The objectives of the study were to identify modifiable risk factors for severe hepatotoxicity following paracetamol overdose in adults. Materials and Methods: A retrospective cohort study involved the consecutive adult patients hospitalized in a toxicological center over a period of seven years due to paracetamol overdose. Complete medical datasets of laboratory and anamnestic variables were analyzed and validated by means of logistic regression model. Results: A total of 185 patients entered the study, including 25 individuals who developed severe hepatotoxicity (plasma aminotransferases levels above 1000 UI/L) and 31 individuals with mild to moderate liver injury (plasma aminotransferases levels above upper normal range, but below 1000 UI/L). In the univariable analysis, significant hepatotoxicity risk factors were male gender, alcohol abuse, an ingested paracetamol dose, and a timespan from ingestion to hospital admission. The later one was the only significant risk factor in the multivariable model (adjusted odds ratio 1.08; 95% CI: 1.03–1.12). Conclusions: A delay in hospital admission, resulting in a delayed administration of disease-specific treatment outweighs any other known risk factors of paracetamol-induced hepatotoxicity.

Hypothalamic Dysregulation; A Hidden Culprit in Multiple Sclerosis Symptoms

Background: A possible association between multiple sclerosis (MS) and dysregulation of hypothalamic-pituitary axis has been reported and its endocrine manifestations can be confused with many nonspecific symptomatology attributed to MS. We report such a case and present the improvement of symptoms independent of MS therapy. Clinical Case: Case of a 45 years-old female with history of type 2 diabetes mellitus, dyslipidemia, HTN, obesity class I and MS that was evaluated for follow up with complaints of fatigue, weakness, somnolence and memory problems. No menstrual disturbances with regular cycles. Denies weight changes, anorexia, nausea, vomiting or abdominal discomfort. Previous hormonal workup showed normal levels of cortisol, ACTH, prolactin and TSH. Nonetheless, on repeated hormonal profile due to nonspecific complaints, patient was found with normal TSH (2.65 mIU/mL, 0.3-3.0 mIU/mL) and low free T4 (0.65 ng/dL, 0.78-2.19 ng/dL). Repeated thyroid function tests by equilibrium dialysis showed a borderline low FT4 (0.8 ng/dL, 0.78-2.19 ng/dL), despite a persistently normal TSH (2.26 mIU/mL, 0.3-3.0 mIU/mL). Suspecting hypopituitarism, a complete hormonal workup revealed a low normal serum cortisol in early morning of 8.39 mcg/dL and ACTH of 16.7 pg/mL, normal prolactin of 10.5 ng/mL and a first IGF-1 evaluation of 68.9 ng/mL, which was low for female age range (98-261 ng/mL). Due to concerns for possible complications during an insulin tolerance test, a cosyntropin stimulation test was performed with adequate peak cortisol response at 30.5 mcg/dL. Most recent brain MRI without pituitary protocol was remarkable for multiple bilateral demyelinating plaques compatible with MS diagnosis that also involved the left thalamus, although no other area adjacent to the hypothalamus or pituitary gland was described. The patient was subsequently started on levothyroxine replacement to a goal of free T4 at the upper normal range, with overall improvement in symptoms and quality of life. Growth hormone status and gonadal axis to be reevaluated. This case emphasizes the importance of clinical judgement and reminds us that overlapping symptoms can lead to misdiagnosis, particularly in conditions with nonspecific symptomatology as MS. Conclusion: This is an unusual case of a patient with multiple sclerosis presenting with hypopituitarism suggesting the possibility of hypothalamic disturbance as the etiology. It has been proposed that demyelinating MS lesions in fiber bundles in and adjacent to the hypothalamus may compromise hypothalamic function. Mechanisms for fatigue in MS have been mostly associated with hyperactivity of HPA axis, not found in our patient. Hypothalamic dysfunction can be frequently overlooked due to overlapping symptoms with MS, despite being a treatable condition that can greatly improve quality of life in these patients.