Serum Fibroblast Growth Factor 23 Levels Research Articles

Fibroblast growth factor 23 and outcomes of atrial fibrillation: from clinical association to genetic evidence.

Fibroblast growth factor 23 (FGF23) has been implicated in the occurrence of atrial fibrillation (AF), but its prognostic value in AF patients remains unclear. A total of 35 197 AF patients with available follow-up data (3.56, 0.47-8.92 years) from the UK Biobank were included. Clinical association between serum FGF23 and AF-related outcomes including mortality, heart failure (HF), ischaemic stroke, and dementia were analysed using multivariable Cox regression. In those passed quality control for array sequencing, polygenic score for FGF23 (PGSFGF23) was calculated as genetic instrument, and the association between PGSFGF23 and the occurrence of endpoints after first AF diagnosis were further explored. In 886 patients who diagnosed AF at or prior to the enrolment, elevated serum FGF23 levels were significantly associated with an increased risk of all-cause (37% increase per standard deviation) and cardiovascular (40% increase per standard deviation) mortality and HF (43% increase per standard deviation). A total of 35 197 patients were available for genetic array sequencing data. Using polygenic score including seven independent SNPs reaching genome-wide significance threshold, genetic association analysis indicated that increased PGSFGF23 is associated with reduced risk of HF but increased risk of all-cause mortality and ischaemic stroke. Our findings suggest that FGF23 is a potential biomarker for accessing AF-related outcomes. The paradoxical association between genetic FGF23 and serum FGF23 level highlights the need for further investigation to elucidate the underlying mechanisms.

The Diagnostic Performance of Fibroblast Growth Factor-21 during Early Stage of Missed Miscarriage

Abstract Background: Missed miscarriages (MMs) occur when an embryo without a cardiac pulse or gestational sac is not expelled from the uterus. Fibroblast growth factor-21 (FGF-21), a member of the fibroblast growth factor family, plays an important regulatory role in metabolism, primarily in glucose and lipid metabolism. Objective: The aim of this study is to investigate whether serum levels of FGF-21 are associated with MM in 8–14 weeks of gestation. Materials and Methods: This case–control study consisted of 88 pregnant women; they were divided into two groups: healthy pregnant (HP), composed of 40 women with a normal viable pregnancy at 8–14 weeks of gestation with mean age (29.07 ± 6.96 years); and study group that included 40 women with MM diagnosed by ultrasound at the same gestational age (GA) with mean age (28.27 ± 7.74 years). Demographic criteria and maternal serum FGF-21 levels were recorded for comparison. ELISA technique was used to measure FGF-21 in circulation. Results: This study revealed a statistically significant increase in serum levels of FGF-21 in MMs (142.47 ± 48.036 pg/ml) compared to normal pregnant women (87.9 ± 30.86). The cutoff point was ≥149.97, with high sensitivity (73.2%) and specificity (97.9%). There was no significant correlation between FGF-21 levels and age, GA, body mass index, or gravidity. Conclusion: The MM group’s serum concentrations of FGF-21 were markedly elevated within a time frame of 8–14 weeks compared to the HP group, suggesting its involvement in the development of MM. Based on the findings, FGF21 demonstrates a remarkable capacity for diagnosing MM.

P0160 Vitamin D and FGF-19 in patients with Inflammatory Bowel Disease

Abstract Background Vitamin D (vit. D) has pleiotropic effects, and in recent years, its role in regulating the immune response has been widely discussed. Patients with IBD tend to have lower vit. D levels, and this may be associated with more frequent relapses, increased need for surgical interventions, and a slower response to antibody treatments. Methods An observational study was conducted at the Gastroenterology Department of UH "Saint Ivan Rilski," Sofia, Bulgaria, involving 47 patients with ulcerative colitis (UC) and 55 with Crohn’s disease (CD). We evaluated serum vit. D, laboratory markers, Fibroblast growth factor-19 (FGF-19) levels. Results Patients with IBD were equally distributed between females (49%) and males (51%). Subnormal vit. D levels were observed in 94% of patients with CD and in 98% of those with UC. This contrasts with the general Bulgarian population, where 76% have lower levels [1]. The mean serum value in patients with IBD was 40 nmol/L, which is insufficient. Vit. D was found to vary depending on treatment. IBD receiving corticosteroids or immunosuppressants had lower levels compared to those treated with biologic agents. The difference was a 13% decrease in CD and 10% in UC. This may be attributed to the inhibitory effects of corticosteroids on vit. D metabolism or the restricted sun exposure when taking azathioprine. The evaluated data revealed that vit. D had a statistically significant inverse correlation with laboratory markers such as C-reactive protein (CRP) (P = 0.0018, r = -0.351), leukocytes (P = 0.0069, r = -0.2661), erythrocyte sedimentation rate (P = 0.0022, r = -0.2992), thrombocytes (P = 0.0083, r = -0.2600), and the neutrophil-to-lymphocyte ratio (NLR) (P = 0.0011, r = -0.3175) and in UC fecal calprotectin (P= 0.0025, r= -0.4025) [2]. Serum FGF-19 levels were evaluated in all IBD and were lower in 8 patients with CD, with a mean level of 20 pg/mL. Six of them had ileocolitis and two had terminal ileitis, which is associated with probable bile acid malabsorption. In other studies was found that patients have bile acid diarrhea with levels of 60pg/mL [3,4]. Statistically significant correlation was observed between FGF-19 and vit. D levels (P = 0.232, r = 0.2836). Conclusion Patients with IBD tend to have insufficient levels of vit. D, due to corticosteroid treatment, reduced sun exposure while taking azathioprine. The role of vit. D in inflammation is worth discussing, as it may have a potential effect on inflammatory markers. In CD is a higher risk of bile acid diarrhea in terminal ileitis or ileocolitis. Serum FGF-19 concentrations in CD may be dependent on vit. D. It is also possible that bile acid diarrhea could be affected by vit. D status.

Correlation between serum levels of fibroblast growth factor-21 and the severity of migraine headache in patients undergoing sodium valproate treatment

Background: Mitochondrial metabolism disruption increases neuron excitability and reduces migraine attack threshold. This study investigates whether serum fibroblast growth factor-21 (FGF-21) levels in chronic migraine relate to headache severity and response to sodium valproate treatment. Methods: This pilot study involved 30 patients with chronic migraine treated with sodium valproate. Serum FGF-21 levels were assessed at baseline and after 12 weeks of treatment. Pain severity and disability were evaluated using visual analogue scale (VAS) and Migraine Disability Assessment (MIDAS). Paired t-test was used for the quantitative variables. The qualitative variables were evaluated using Pearson’s chi-square test and Fisher’s exact test. Moreover, correlation coefficients were calculated. A P < 0.05 was considered statistically significant. Results: Mean age of the patients was 42.9 ± 11.3 years. There was a significant reduction in headache severity between baseline and the end of the study regarding VAS scores (8.50 ± 1.50 vs. 5.30 ± 2.20, P < 0.001). The same reduction was observed in MIDAS during the study (61.20 ± 33.20 vs. 20.31 ± 17.07, P < 0.001). However, there was no significant changes in serum levels of FGF-21 over three months (299.53 ± 479.80 vs. 491.33 ± 456.64, P = 0.810), nor any relationship between these levels and headache severity scores (MIDAS: P = 0.658, VAS: P = 0.708). Conclusion: The results of this study did not show a significant correlation between FGF-21 serum levels and changes in VAS and MIDAS throughout the study. Further research on various mitochondrial pathways can provide valuable insights into the migraine pathophysiology and help identify more effective biomarkers for monitoring therapeutic regimens.

Role of serum fibroblast growth factor-23 and Klotho level in COVID-19 infection-related mortality: a prospective study.

This study investigated the role of fibroblast growth factor 23 (FGF23)/Klotho in the mortality of patients hospitalized with coronavirus disease 2019 (COVID-19), excluding those with chronic kidney disease (CKD). A prospective cross-sectional study was conducted from April 2021 to May 2022. Patients who tested positive for COVID-19 via polymerase chain reaction and were hospitalized, were classified into two groups (survivors and non-survivors) at the end of their hospital follow-up. Demographic data, clinical status, and prognosis were analyzed. A total of 66 patients (age 58.8 ± 17.0 years, 60.6% male) were included. The mean age of non-survivors (67.2 ± 1 years) was significantly higher than the survivors (49.2 ± 1 years; p < 0.0001). FGF23 was significantly elevated in non-survivors (301 ± 20 pg/mL), compared to survivors (160 ± 36 pg/mL; p < 0.0001). Factors with significant differences (p < 0.001) between the two groups were investigated as independent mortality predictors using logistic regression analysis. FGF23 (p = 0.01), age (p = 0.045), and oxygen saturation at admission (p = 0.02) were independent predictors of mortality. High serum FGF23 levels were associated with COVID-19-related mortality; Klotho levels were lower (p = 0.028). Vitamin D was not significantly different between the groups. Elevated serum FGF23 and parathyroid hormone (PTH), and lower Klotho levels, were associated with COVID-19-related mortality in patients without CKD. There was no association with serum vitamin D levels. Further studies are required to establish the relationship between mortality and FGF23/Klotho, PTH, and vitamin D levels.

Sulfur Amino Acid Restriction Mitigates High-Fat Diet-Induced Molecular Alterations in Cardiac Remodeling Primarily via FGF21-Independent Mechanisms.

Background/Objectives: Dietary sulfur amino acid restriction (SAAR) elicits various health benefits, some mediated by fibroblast growth factor 21 (FGF21). However, research on SAAR's effects on the heart is limited and presents mixed findings. This study aimed to evaluate SAAR-induced molecular alterations associated with cardiac remodeling and their dependence on FGF21. Methods: Male C57BL/6J wild-type and FGF21 knockout mice were randomized into four dietary regimens, including normal fat and high-fat diets (HFDs) with and without SAAR, over five weeks. Results: SAAR significantly reduced body weight and visceral adiposity while increasing serum FGF21 levels. In the heart, SAAR-induced molecular metabolic alterations are indicative of enhanced lipid utilization, glucose uptake, and mitochondrial biogenesis. SAAR also elicited opposing effects on the cardiac gene expression of FGF21 and adiponectin. Regarding cellular stress responses, SAAR mitigated the HFD-induced increase in the cardiac expression of genes involved in oxidative stress, inflammation, and apoptosis, while upregulating antioxidative genes. Structurally, SAAR did not induce alterations indicative of cardiac hypertrophy and it counteracted HFD-induced fibrotic gene expression. Overall, most alterations induced by SAAR were FGF21-independent, except for those related to lipid utilization and glucose uptake. Conclusions: Altogether, SAAR promotes cardiac alterations indicative of physiological rather than pathological remodeling, primarily through FGF21-independent mechanisms.

Serum fibroblast growth factor 21: Lack of association with gestational diabetes and pregnancy outcomes

BACKGROUND The prevalence of gestational diabetes mellitus (GDM) has been increasing worldwide and is associated with multiple adverse pregnancy outcomes. Despite standard screening, some cases remain undiagnosed. Fibroblast growth factor 21 (FGF21) plays a role in modulating glucose metabolism. There is an ongoing controversy regarding the relevance of FGF21 to GDM. AIM To evaluate the association between early second trimester serum FGF21 levels and gestational diabetes, and its predictive potential for outcomes. METHODS This cross-sectional observational study was conducted at a tertiary medical center, Chiang Mai University, Thailand. It included 28 pregnant women diagnosed with GDM and 81 pregnant women with normal glucose status. Blood samples were collected according to the study schedule, and pregnancy outcomes were recorded meticulously. Descriptive analysis was employed to evaluate the data. RESULTS Most participants in our study had no risk factors for GDM (body mass index &lt; 24 kg/m2, no first-degree relatives with diabetes, no history of GDM), normal baseline glucose status (fasting glucose &lt; 110 mg/dL), and no insulin resistance (homeostatic model assessment of insulin resistance &lt; 2). There was a trend of increased FGF21 levels in the insulin-treated GDM group compared with dietary-treated GDM and non-GDM (73.58 pg/mL vs 62.94 pg/mL vs 63.59 pg/mL, respectively, P = 0.73). However, no significant association was found between FGF21 concentrations and pregnancy outcomes based on quintiles of FGF21 levels. CONCLUSION FGF21 was not associated with GDM or pregnancy outcomes; however, due to the small sample size, larger clinical trials with a diverse population are suggested to confirm these results.

The Effect of Ferric Carboxymaltose on Fibroblast Growth Factor 23 (FGF23) in Children with Iron Deficiency Anemia Due to Gastrointestinal Diseases

Background: Hypophosphatemia is a known side-effect of parenteral iron administration, especially after intravenous ferric carboxymaltose (FCM). Fibroblast growth factor 23 (FGF23) is thought to play an important role in the pathophysiology of serum phosphate homeostasis. This study aimed to investigate the effects of FCM on FGF23 serum levels in FCM-treated pediatric patients with iron deficiency (ID)/iron deficiency anemia (IDA) caused by gastrointestinal diseases. Methods: Over 30 months, FGF23 serum levels were assessed prospectively in children with ID/IDA due to gastrointestinal diseases and treated with FCM infusion. Serum levels of intact FGF23 (iFGF23) were assessed and correlated to phosphate serum levels and factors of bone metabolism. Blood sampling was performed in three phases: before FCM infusion, 7–10 days after FCM infusion, and 6–8 weeks after FCM infusion. Results: A total of 42 FCM infusions were given to 35 children (20 girls) with a mean age (±SD) of 12.2 (±4.03) years (range: 2–16 years). The median levels of iFGF23 did not show a significant difference across the three phases (p = 0.56). No significant correlation was found between iFGF23 levels and 25-hydroxyvitamin D/parathyroid hormone/serum phosphate/serum calcium/alkaline phosphatase. No significant change was noted between pre- and post-treatment serum phosphate levels. However, four children (11.42%) developed asymptomatic and transient hypophosphatemia. Conclusions: No significant difference was found between pre-and post-FCM infusion serum iFGF23 levels and bone metabolism parameters. An increase of iFGF23 serum levels 7–10 days after FCM infusion was noted in patients with hypophosphatemia.

Relationship of Serum Fibroblast Growth Factor 23, Hypoxia-Inducible Factor-1α, and Klotho with In-Stent Restenosis in Elderly Patients with Coronary Artery Disease after the Treatment of Percutaneous Coronary Intervention.

In-stent restenosis (ISR) commonly occurs in elderly patients with coronary artery disease (CAD) after percutaneous coronary intervention. Atherosclerosis in elderly patients may be the leading cause of ISR. Therefore, we aim to explore the relationship between vascular calcification-associated factors and ISR occurrence. Elderly patients were enrolled according to standard inclusion and exclusion criteria. The serum fibroblast growth factor 23 (FGF23), hypoxia-inducible factor-1α (HIF-1α), and Klotho levels were determined using an enzyme-linked immunosorbent assay. The degree of coronary artery stenosis of the patients with CAD before operation was assessed using the Gensini score. The correlation was analyzed using Pearson analysis. The prediction value was evaluated using receiver operating characteristic (ROC) curve analysis. The patients with CAD were classified into the ISR group with 97 cases and the non-ISR (NISR) group with 349 cases. The Gensini score, serum FGF23, and HIF-1α levels increased while Klotho levels decreased in patients with CAD of the ISR group compared with those of the NISR group. Pearson analysis showed that FGF23 and HIF-1α positively correlated while Klotho negatively correlated to the Gensini score. ROC analysis showed all three factors could effectively predict the occurrence of ISR. Furthermore, the joint had a more effective prediction value for ISR occurrence. The dynamic analysis presented that the serum FGF23 and HIF-1α levels dramatically increased while Klotho levels decreased in patients with CAD after 1-year follow-up. Serum FGF23 and HIF-1α positively correlated while serum Klotho negatively correlated to ISR. Conclusively, these three factors effectively predicted the occurrence of ISR.

The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23

Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, and increased FGF23 levels result in hypophosphatemia; however, the molecular mechanism underlying increased FGF23 expression has not been fully elucidated. In this study, we found that mice lacking the bobby sox homolog (Bbx−/−) presented increased FGF23 expression and low phosphate levels in the serum and skeletal abnormalities such as a low bone mineral density (BMD) and bone volume (BV), as well as short and weak bones associated with low bone formation. Osteocyte-specific deletion of Bbx using Dmp-1-Cre resulted in similar skeletal abnormalities, elevated serum FGF23 levels, and reduced serum phosphate levels. In Bbx−/− mice, the expression of sodium phosphate cotransporter 2a (Npt2a) and Npt2c in the kidney and Npt2b in the small intestine, which are negatively regulated by FGF23, was downregulated, leading to phosphate excretion/wasting and malabsorption. An in vitro Fgf23 promoter analysis revealed that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced transactivation of the Fgf23 promoter was significantly inhibited by BBX overexpression, whereas it was increased following Bbx knockdown. Interestingly, 1,25(OH)2D3 induced an interaction of the 1,25(OH)2D3 receptor (VDR) with BBX and downregulated BBX protein levels. Cycloheximide (CHX) only partially downregulated BBX protein levels, indicating that 1,25(OH)2D3 regulates BBX protein stability. Furthermore, the ubiquitination of BBX followed by proteasomal degradation was required for the increase in Fgf23 expression induced by 1,25(OH)2D3. Collectively, our data demonstrate that BBX negatively regulates Fgf23 expression, and consequently, the ubiquitin-dependent proteasomal degradation of BBX is required for FGF23 expression, thereby regulating phosphate homeostasis and bone development in mice.

The potential of fibroblast growth factor-21 and adiponectin as diagnostic biomarkers for type 2 diabetes mellitus: differential levels in response to treatments

BackgroundDiabetes mellitus (DM) is a global epidemic disease affecting millions each year. Recent studies have suggested novel biomarkers that are linked to DM. This study aimed to measure the levels of fibroblast growth factor-21 (FGF-21) and adiponectin in the blood of patients with type 2 DM and to assess the variations in their levels in response to the type of treatments. The possible correlations with several biochemical parameters and the diagnostic potential of FGF-21 and adiponectin as biomarkers for DM were also investigated. Eighty subjects were classified into control, Type 2 DM patients who were treated with metformin, Type 2 DM patients who were treated with metformin + oral hypoglycemic agents (OHAs), and Type 2 DM patients who were treated with insulin + metformin + OHAs.ResultsThe metformin + OHAs group and the insulin + metformin + OHAs group had higher levels of FGF-21 when compared to the control group. The metformin + OHAs also had significantly higher adiponectin levels when compared to the control or metformin groups. The serum levels of FGF-21 in the diabetic subjects were negatively correlated with LDL, direct bilirubin, albumin, and insulin levels and positively correlated with the duration of DM. However, the serum levels of adiponectin in the diabetic subjects were negatively correlated with weight while positively correlated with potassium levels. Remarkably, FGF-21 and adiponectin were effective biomarkers for diagnosing DM with a specificity of 100% and 90% and sensitivity of 52.3% and 64.5%, respectively.ConclusionThese findings suggest that FGF-21 and adiponectin play crucial roles in DM diagnosis and prognosis and that their levels change depending on the treatment type.

Causal association of serum calcium, phosphate, vitamin D, parathyroid hormone, and FGF23 with the risk of aortic stenosis

Abstract Aim Disorders of mineral metabolism, including elevated levels of serum calcium, phosphate, 25-hydroxyvitamin D (25OH-VitD), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), have been reported in patients with calcific aortic valve stenosis (CAVS). However, evidence of the causal role of mineral metabolism in CAVS is still lacking. We aimed to investigate the causality between mineral metabolism and CAVS. Methods A systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis was applied to investigate the causal effect. Genome-wide association study (GWAS) and protein quantitative trait loci data for mineral metabolism markers were extracted from large-scale meta-analyses. Summary statistics for CAVS were obtained from two independent GWAS datasets as discovery and replication cohorts (n=374,277 and 653,867). Results In MR analysis, genetic mimicry of serum FGF23 elevation was associated with increased CAVS risk [ORdiscovery=3.081 (1.649-5.760), Pdiscovery=4.21×10-4; ORreplication=2.280 (1.461-3.558), Preplication=2.82×10-4] without evidence of reverse causation (Psteiger=7.21×10-98). Strong colocalisation association with CAVS was observed for FGF23 expression in the blood (PP.H4 = 0.96). Additionally, we identified some protein-protein interactions between FGF23 and known CAVS causative genes. Serum calcium, phosphate, 25OH-VitD, and PTH failed to show causal effects on CAVS at Bonferroni-corrected significance (all P&amp;gt;0.05/5=0.01). Conclusions Elevated serum FGF23 level is a causal risk factor for CAVS, and its mechanism of action in CAVS development may be independent of its function in regulating mineral metabolism. Hence, FGF23 may serve as a circulating marker and a promising preventive target for CAVS, warranting further investigation.

Low Serum Fibroblast Growth Factor 21 Level and Its Altered Regulation by Thyroid Hormones in Patients with Hashimoto's Thyroiditis on Levothyroxine Substitution.

Fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism exerting protection against atherosclerosis by multiple actions on the blood vessels, liver, and adipose tissues. We aimed to investigate serum FGF21 level and its relation to thyroid hormones and metabolic parameters among patients with Hashimoto's thyroiditis (HT). Eighty patients with HT on levothyroxine treatment and eighty-two age- and BMI-matched adults without thyroid disease serving as controls were enrolled. Serum FGF21 concentrations were determined with an enzyme-linked immunosorbent assay. Median serum FGF21 level was significantly lower in HT patients compared with controls (74.2 (33.4-148.3) pg/mL vs. 131.9 (44.8-236.3) pg/mL; p = 0.03). We found a positive correlation between FGF21 and age, triglyceride, total cholesterol, and low-density lipoprotein cholesterol in both groups, while thyroid stimulating hormone and C-reactive protein showed a positive correlation, and thyroxine had an inverse correlation with FGF21 only in control subjects. According to multiple regression analyses, thyroid status is the main predictor of FGF21 in healthy controls, while it is not a significant predictor of FGF21 among HT patients on levothyroxine supplementation therapy. Our results indicate that the physiological role of thyroid function in the regulation of FGF21 synthesis is impaired in HT patients, which may contribute to the metabolic alterations characteristic of HT patients.

Evaluation of alpha Klotho and fibroblast growth factor-23 levels in Iraqi patients with Graves’ disease

Background &amp; Objective: Graves’ disease (GD) is an autoimmune condition that targets the thyroid gland, resulting in excessive stimulation and synthesis of thyroid hormones. Excessive synthesis of these hormones can lead to symptoms such as loss of body weight, accelerated heart rate, irritability, reduced tolerance to heat, and excessive perspiration. Alpha-Klotho (KL), a protein crucial for physiological processes, is also involved in GD. The defective immunological condition of GD patients may increase Klotho expression, and the enhanced expression of fibroblast growth factor-23 (FGF23) in GD may be linked to the disease pathophysiology. We investigated serum levels of KL and FGF23 in Iraqi patients with Graves’ disease, analyzing correlations with clinical status and evaluating their potential as biomarkers for disease activity. Methodology: We conducted this cross-sectional study at The National Diabetes Center, Mustansiriyah University, between December 2022 and April 2023. The study involved 103 patients diagnosed with GD, and 103 patients, aged 21-70 y, as a control group. Patients with multinodular goiter, single thyroid nodules, thyroiditis, pregnant women, and those on medications or oral contraceptives, were excluded. Result: clinical significance of FGF23 and Klotho (KL) levels in patients with Graves’ disease (GD) compared to a control group. Results indicate that the median of KL levels are significantly higher in GD patients (KL = 6.31) compared to the control group (KL = 2.40), with a highly significant difference (P &lt; 0.001). In contrast, differences in median of FGF23 levels between GD patients (149) and controls (86.05) were not statistically significant (P = 0.07). Furthermore, KL levels were significantly higher in hyperthyroid patients compared to other thyroid statuses (P = 0.023), while FGF23 levels did not significantly differ across thyroid statuses (P = 0.255). Additionally, the study found a strong correlation between TRAb levels and both KL (r = 0.291, P &lt; 0.001) and FGF23 (r = 0.211, P = 0.003), and between KL and FGF23 directly (r = 0.412, P &lt; 0.001). These findings suggest that while KL may be a significant biomarker in GD, FGF23 relevance appears limited in this context. Conclusion: In Graves’ Disease patients have significantly higher levels of KL and FGF23 compared to controls, suggesting a distinct pathophysiological role for these biomarkers in mineral homeostasis and thyroid hormone regulation. Abbreviations: AITD - Autoimmune thyroid diseases; KL - Alpha-Klotho; FGF23 - fibroblast growth factor-23; GD - Graves’ disease; HT - Hashimoto's thyroiditis; IGF-1R - Insulin-like Growth Factor-1 Receptor; Keywords: Autoimmune Thyroid Disorders, Hyperthyroidism, Graves’ disease, Alpha-Klotho Citation: Rashid MF, Alammar HAJ, Rahmah AM. Evaluation of alpha Klotho and fibroblast growth factor-23 levels in Iraqi patients with Graves’ disease. Anaesth. pain intensive care 2024;28(5):836−841. DOI: 10.35975/apic.v28i5.2567 Received: June 16, 2024; Reviewed: July 07, 2024; Accepted: July 18, 2024

7492 Fibroblast Growth Factor 21 In The Diagnosis And Treatment Of Metabolic Disorders

Abstract Disclosure: H.M. Heshmati: None. H.S. Abu-Lebdeh: None. Background: Fibroblast growth factor 21 (FGF21), a member of the human FGF superfamily, is a 181 amino acid peptide hormone primarily produced by the liver. The gene of FGF21, located on chromosome 19, was cloned in 2000. FGF21 is involved in the maintenance of metabolic homeostasis. This review presents an update on the relevance of FGF21 in the diagnosis and treatment of metabolic disorders including obesity, nonalcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes. Methods: A systematic search of literature was conducted using the search terms fibroblast growth factor 21, obesity, nonalcoholic fatty liver disease, dyslipidemia, and type 2 diabetes. Results: FGF21 is a stress hormone with effects on energy expenditure and metabolism of lipids and glucose. FGF21 exerts its endocrine action in the central nervous system and adipose tissue. The serum FGF21 levels in normal subjects increase with aging. Stressful conditions (e.g., fasting status, protein restriction, exercise, metabolic disorders, kidney diseases, cardiovascular diseases, and sepsis) increase FGF21 secretion. Serum FGF21 levels are increased in obesity, NAFLD, dyslipidemia, and type 2 diabetes. Some of these patients may have a state of FGF21 resistance. The resistance to FGF21 is related, at least in part, to the presence of high circulating levels of fibroblast activation protein, a protease that inactivates FGF21. It has been suggested that the exercise-induced weight loss can be due to increased FGF21 secretion and decreased FGF21 resistance in adipose tissue. Serum FGF21 level has the potential to be used as a biomarker for early diagnosis of metabolic disorders (e.g., NAFLD and type 2 diabetes). Based on different metabolic properties of FGF21, FGF21-based therapy has been considered as an attractive approach for the treatment of metabolic disorders. Since native FGF21 has poor pharmacodynamic properties (e.g., short half-life and proteolytic cleavage by proteases), long-acting FGF21 analogs (e.g., LY2405319, PF-05231023, pegozafermin, AKR-001, and LLF580) have been synthesized and tested in clinical trials for the treatment of obesity, NAFLD, dyslipidemia, and type 2 diabetes. The available results show that FGF21 analogs can reduce body weight, liver fat, blood lipids, and fasting insulin/insulin resistance. Overall, the treatment with these analogs is safe and well tolerated. Conclusion: FGF21 is a predominantly liver-derived peptide hormone regulating energy expenditure and metabolism of lipids and glucose. Serum FGF21 levels are increased in several metabolic disorders including obesity, NAFLD, dyslipidemia, and type 2 diabetes. FGF21 is an attractive target for the treatment of these metabolic disorders. Despite some promising results observed with the use of FGF21 analogs, more clinical studies are needed before recommending FGF21-based therapies in metabolic disorders. Presentation: 6/2/2024

Prostaglandin E2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production

Bone cells produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D homeostasis, and a paracrine factor produced in further tissues. Chronic kidney disease and cardiovascular disorders are associated with early elevations of plasma FGF23 levels associated with clinical outcomes. FGF23 production is dependent on many conditions including inflammation. Prostaglandin E2 (PGE2) is a major eicosanoid with a broad role in pain, inflammation, and fever. Moreover, it regulates renal blood flow, renin secretion, natriuresis as well as bone formation through prostaglandin E receptor 2 (EP2). Here, we studied the role of PGE2 and its signaling for the production of FGF23. Osteoblast-like UMR-106 cells were exposed to EP receptor agonists, antagonists or RNAi. Wild type and EP2 knockout mice were treated with stable EP2 agonist misoprostol. Fgf23 or Nurr1 gene expression was determined by quantitative real-time PCR, hormone and further blood parameters by enzyme-linked immunosorbent assay and colorimetric methods. PGE2 and EP2 agonists misoprostol and butaprost enhanced FGF23 production in UMR-106 cells, effects mediated by EP2 and transcription factor Nurr1. A single dose of misoprostol up-regulated bone Fgf23 expression and FGF23 serum levels in wild type mice with subtle effects on parameters of mineral metabolism only. Compared to wild type mice, the FGF23 effect of misoprostol was significantly lower in EP2-deficient mice. To conclude, PGE2 signaling through EP2 and Nurr1 induces FGF23 production. Given the broad physiological and pathophysiological implications of PGE2 signaling, this effect is likely of clinical relevance.

Clinical value of fibroblast growth factor 19 in predicting gastrointestinal dysfunction in patients with sepsis.

To assess the potential value of fibroblast growth factor 19 (FGF19) as a predictor of gastrointestinal (GI) dysfunction in patients with sepsis. A prospective study was conducted, and 209 patients who were diagnosed with sepsis and admitted to the intensive care unit (ICU) at teaching hospitals in China were enrolled from June 2023 to December 2023. The serum FGF19 level was determined at ICU admission. The differences in serum FGF19 levels between the two groups were compared via the Mann-Whitney U test, and Spearman's correlation coefficient was used to identify the correlations of the FGF19 concentration with other clinical variables and biomarkers. Receiver operating characteristic (ROC) analysis was used to determine the value of FGF19 in predicting GI dysfunction in patients with sepsis. The total ICU mortality rate was 13.3% (24/180). There was a tendency toward increased ICU mortality in patients with sepsis-associated GI dysfunction compared with patients without GI dysfunction with statistical significance (21.9% vs. 8.6%, p = 0.031). Serum FGF19 levels were significantly higher in patients with sepsis-associated GI dysfunction than in patients without GI dysfunction [355.1 (37.2, 2315.4) μg/mL vs. 127.4 (5.7, 944.2) μg/mL, p = 0.003]. The results of receiver operating characteristic (ROC) curve analysis revealed that the area under the ROC curve (AUC) for the ability of FGF19 to predict GI dysfunction in patients with sepsis was 0.773 (95% CI 0.712 ~ 0.827), which was greater than the predictive capacity of PCT [AUC = 0.632 (95% CI 0.562 ~ 0.804)]. Serum FGF19 could be considered as a novel predictor or biomarker of GI dysfunction in patients with sepsis.

Genetic association of serum calcium, phosphate, vitamin D, parathyroid hormone, and FGF23 with the risk of aortic stenosis

Disorders of mineral metabolism, including elevated levels of serum calcium, phosphate, 25-hydroxyvitamin D (25OH-VitD), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), have been reported in patients with calcific aortic valve stenosis (CAVS). However, evidence of the causal role of mineral metabolism in CAVS is still lacking. In this study, we employed a systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis to investigate the causal effect of mineral metabolism on CAVS. Genome-wide association study (GWAS) and protein quantitative trait loci data for mineral metabolism markers were extracted from large-scale meta-analyses. Summary statistics for CAVS were obtained from two independent GWAS datasets as discovery and replication cohorts (n = 374,277 and 653,867). In MR analysis, genetic mimicry of serum FGF23 elevation was associated with increased CAVS risk [ORdiscovery = 3.081 (1.649–5.760), Pdiscovery = 4.21 × 10−4; ORreplication = 2.280 (1.461 – 3.558), Preplication = 2.82 × 10−4] without evidence of reverse causation (Psteiger= 7.21 × 10−98). Strong colocalisation association with CAVS was observed for FGF23 expression in the blood (PP.H4 = 0.96). Additionally, we identified some protein-protein interactions between FGF23 and known CAVS-associated genes. Serum calcium, phosphate, 25OH-VitD, and PTH failed to show causal effects on CAVS at Bonferroni-corrected significance (all P > 0.05/5 = 0.01). In conclusion, elevated serum FGF23 level may act as a causal risk factor for CAVS, and its mechanism of action in CAVS development may be independent of its function in regulating mineral metabolism. Hence, FGF23 may serve as a circulating marker and a promising preventive target for CAVS, warranting further investigation.

Connecting the Dots: FGF21 as a Potential Link between Obesity and Cardiovascular Health in Acute Coronary Syndrome Patients.

Fibroblast growth factor 21 (FGF21) is a hormone involved in regulating the metabolism, energy balance, and glucose homeostasis, with new studies demonstrating its beneficial effects on the heart. This study investigated the relationship between FGF21 levels and clinical, biochemical, and echocardiographic parameters in patients with acute coronary syndromes (ACSs). This study included 80 patients diagnosed with ACS between May and July 2023, categorized into four groups based on body mass index (BMI): Group 1 (BMI 18.5-24.9 kg/m2), Group 2 (BMI 25-29.9 kg/m2), Group 3 (BMI 30-34.9 kg/m2), and Group 4 (BMI ≥ 35 kg/m2). Serum FGF21 levels were measured by ELISA (Abclonal Catalog NO.: RK00084). Serum FGF21 levels were quantifiable in 55 samples (mean ± SD: 342.42 ± 430.17 pg/mL). Group-specific mean FGF21 levels were 238.98 pg/mL ± SD in Group 1 (n = 14), 296.78 pg/mL ± SD in Group 2 (n = 13), 373.77 pg/mL ± SD in Group 3 (n = 12), and 449.94 pg/mL ± SD in Group 4 (n = 16), with no statistically significant differences between groups (p = 0.47). Based on ACS diagnoses, mean FGF21 levels were 245.72 pg/mL for STEMI (n = 21), 257.89 pg/mL for NSTEMI (n = 9), and 456.28 pg/mL for unstable angina (n = 25), with no significant differences observed between these diagnostic categories. Significant correlations were identified between FGF21 levels and BMI, diastolic blood pressure, and serum chloride. Regression analyses revealed correlations with uric acid, chloride, and creatinine kinase MB. This study highlights the complex interplay between FGF21, BMI, and acute coronary syndromes. While no significant differences were found in FGF21 levels between the different BMI and ACS diagnostic groups, correlations with clinical and biochemical parameters suggest a multifaceted role of FGF21 in cardiovascular health. Further research with a larger sample size is warranted to elucidate these relationships.

FGF-21 Level is higher in patients with breast cancer, a candidate for a new biomarker?

Aims: Fibroblast Growth Factor 21 (FGF-21) is a member of the FGF family involved in biological processes such as embryonic development. cell growth. morphogenesis. tissue repair. tumour growth and invasion. with mitogenic and cytogenetic activity at 19q13.33.Breast cancer is a deadly and increasing disease in women. and recent studies have shown a relationship between some cancers. including breast cancer. and hormones secreted from adipose tissue.The aim of the present study was the measurement of FGF-21 levels in patients with breast cancer and its association with breast cancer. Methods: The study included 39 patients with newly diagnosed breast cancer and 39 healthy controls. During the patients’ routine blood tests. a venous blood sample was taken and the serum levels of FGF-21 were determined by ELISA. Results: Demographic and laboratory data were compared between the newly diagnosed breast cancer group and the control group. The control group consisted of 39 participants with a mean age of 52.49 ± 7.02 years. In the patient group. 39 participants with a mean age of 52.15 ± 6.21 years were included in the study. there was no statistical difference regarding age(p&gt;0.05).In the control group. the mean FGF-21 level was 121.35 ± 88.4 pg/ml. while the mean FGF-21 level in the patient group was 171 ± 117.45 pg/ml. a statistically significant difference was detected(p value=0.036). Conclusion: FGF-21 is thought to have significant and beneficial effects on glucose. lipid and energy metabolism. as well as slowing the growth of cancer cells. and may later be used as a biological marker for breast cancer.