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![Schematic representation of bilirubin metabolism. Heme released from senescent red blood cells can be readily oxidized by heme oxygenase to biliverdin, which is subsequently reduced to bilirubin by biliverdin reductase. Biliverdin reductase is found in all tissues under physiological conditions, but especially in reticuloendothelial macrophages of the kidney, spleen, liver and brain [5]. Bilirubin binds to albumin and is then transported to the liver, where it is conjugated by UGT1A1 with UDP-glucuronic acid to increase its solubility in water. Abbreviations: CO, carbon monoxide; NADP + , nicotinamide adenine dinucleotide phosphate; NADPH, the reduced form of NADP + ; RBCs, red blood cells; UDP, uridine diphosphate; UGT1A1; uridine diphosphate-glucuronyl transferase 1A1.](publication/330031140/figure/fig1/AS:710082140590081@1546308183111/Schematic-representation-of-bilirubin-metabolism-Heme-released-from-senescent-red-blood.jpg)
Schematic representation of bilirubin metabolism. Heme released from senescent red blood cells can be readily oxidized by heme oxygenase to biliverdin, which is subsequently reduced to bilirubin by biliverdin reductase. Biliverdin reductase is found in all tissues under physiological conditions, but especially in reticuloendothelial macrophages of the kidney, spleen, liver and brain [5]. Bilirubin binds to albumin and is then transported to the liver, where it is conjugated by UGT1A1 with UDP-glucuronic acid to increase its solubility in water. Abbreviations: CO, carbon monoxide; NADP + , nicotinamide adenine dinucleotide phosphate; NADPH, the reduced form of NADP + ; RBCs, red blood cells; UDP, uridine diphosphate; UGT1A1; uridine diphosphate-glucuronyl transferase 1A1.
Source publication
Bilirubin is a well-known neurotoxin in newborn infants; however, current evidence has shown that a higher serum bilirubin concentration in physiological ranges is associated with a lower risk for the development and progression of both chronic kidney disease (CKD) and cardiovascular disease (CVD) in adults. The protective mechanisms of bilirubin i...
Contexts in source publication
Context 1
... oxygenase (HO), a rate-limiting enzyme in heme catabolism, cleaves heme to form biliverdin, which is subsequently converted by biliverdin reductase into bilirubin [1,2]. Bilirubin binds to albumin in the circulation and is transported to the liver, where it is conjugated by uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) with glucuronic acid and excreted into bile mediated by multi-drug resistance protein-2 ( Figure 1) [3,4]. Once entering the bile canaliculi, conjugated bilirubin is stored and mixed with the other constituents of bile in the gall bladder. ...
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Citations
... Even if very high levels result in neurotoxic effects, bilirubin has been demonstrated to have different beneficial effects, such as antioxidant [48], anti-carcinogenesis [49], immunomodulatory [50], and anti-inflammatory effects on the CV system [51]. Moreover, it is involved in the regulation of several signaling pathways, thanks to its ability to bind receptors like aryl hydrocarbon receptor (AHR); CAR; Mas-related G protein-coupled receptor (MRGPR); peroxisome proliferator-activated receptor α (PPARα); peroxisome proliferator-activated receptor γ (PPARγ), thus acting as a hormone for energy homeostasis and lipid metabolism [39]. ...
Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs/bilirubin and CVD were examined in depth to better interpret the possible link between them.
... 822 a protective role in cardiovascular diseases; an inverse association between circulating total bilirubin level and CVD risk was detected independent of established risk factors. [20][21][22][23] In our study, an acute elevation of bilirubin (range 15.96±9.42 umol/L from 23.90±13.80 ...
Background
The role of total bilirubin (TBIL) in cardiovascular disease has been increasingly recognized in recent decades. Studies have shown a correlation between total bilirubin levels and the prognosis of patients after heart surgery. This study aimed to investigate the clinical significance of bilirubin elevation in persistent atrial fibrillation (PAF) patients who received radiofrequency catheter ablation (RFCA).
Methods and Results
A total of 184 patients with PAF who received RFCA were retrospectively studied. Laboratory examinations and demographic data were analyzed to identify independent predictors of TBIL elevation. The relationship between TBIL and prognosis was further investigated. Our results indicated that TBIL increased significantly after RFCA. Multiple linear regression analysis showed that TBIL elevation owned a negative correlation with the percentile of low voltage areas (LVAs) in left atria (β=−0.490, P<0.001). In contrast, a positive correlation was observed with the white blood cell (WBC) ratio (β=0.153, P=0.042) and left atrial diameter (LAD) (β=0.232, P=0.025). It was found that postoperative TBIL levels increased and then gradually decreased to baseline within 5 days without intervention. The bilirubin ratio <1.211 indicated the possibility of 1-year AF recurrence after ablation with a predictive value of 0.743 (specificity = 75.00%, sensitivity = 66.67%).
Conclusion
Bilirubin elevation post PAF RFCA was a common phenomenon and was associated with 1-year recurrence of AF in PAF patients after RFCA.
... Bilirubin is a bile pigment synthesized endogenously, and its accumulation in the body could be toxic. An increase in the conjugated bilirubin concentration of serum reflects a distorted balance between the rate of haem conversion to bilirubin and the capacity of the liver to produce conjugated bilirubin [18,19]. In this study, total bilirubin and conjugated bilirubin in males were slightly (statistically insignificant) higher than in females, while unconjugated bilirubin in females was significantly higher than in males. ...
... Bilirubin, a byproduct of normal Hb breakdown that plays an important physiologic role as a strong antioxidant and antiinflammatory molecule through efficiently scavenging of peroxyl radicals and suppression of oxidation, inhibiting platelets, and regulating immunity (57), has been demonstrated to be involved in the development and progression of DKD (58). The present study provided evidence that inflammation and oxidative stress correlated with DKD and its distinct phenotypes, since we found that T2DM patients with DKD had significantly higher neutrophil count, and lower lymphocyte count, TBIL, and Hb than those with non-DKD, and neutrophil count was further increased and lymphocyte count, TBIL, and Hb were further decreased in T2DM patients with DKD-non-Alb and DKD stage 3 Alb compared to those with DKD stages 1-2 Alb, and TBIL and Hb were independently significantly associated with the presence of DKD. ...
Objective
Systemic immune-inflammation index (SII), a novel inflammatory marker, has been reported to be associated with diabetic kidney disease (DKD) in the U.S., however, such a close relationship with DKD in other countries, including China, has not been never determined. We aimed to explore the association between SII and DKD in Chinese population.
Methods
A total of 1922 hospitalized patients with type 2 diabetes mellitus (T2DM) included in this cross-sectional study were divided into three groups based on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR): non-DKD group, DKD stages 1–2 Alb group, and DKD-non-Alb+DKD stage 3 Alb group. The possible association of SII with DKD was investigated by correlation and multivariate logistic regression analysis, and receiver-operating characteristic (ROC) curves analysis.
Results
Moving from the non-DKD group to the DKD-non-Alb+DKD stage 3 Alb group, SII level was gradually increased ( P for trend <0.01). Partial correlation analysis revealed that SII was positively associated with urinary ACR and prevalence of DKD, and negatively with eGFR (all P <0.01). Multivariate logistic regression analysis showed that SII remained independently significantly associated with the presence of DKD after adjustment for all confounding factors [(odds ratio (OR), 2.735; 95% confidence interval (CI), 1.840-4.063; P < 0.01)]. Moreover, compared with subjects in the lowest quartile of SII (Q1), the fully adjusted OR for presence of DKD was 1.060 (95% CI 0.773-1.455) in Q2, 1.167 (95% CI 0.995-1.368) in Q3, 1.266 (95% CI 1.129-1.420) in the highest quartile (Q4) ( P for trend <0.01). Similar results were observed in presence of DKD stages 1–2 Alb or presence of DKD-non- Alb+DKD stage 3 Alb among SII quartiles. Last, the analysis of ROC curves revealed that the best cutoff values for SII to predict DKD, Alb DKD stages 1- 2, and DKD-non-Alb+ DKD stage 3 Alb were 609.85 (sensitivity: 48.3%; specificity: 72.8%), 601.71 (sensitivity: 43.9%; specificity: 72.3%), and 589.27 (sensitivity: 61.1%; specificity: 71.1%), respectively.
Conclusion
Higher SII is independently associated with an increased risk of the presence and severity of DKD, and SII might be a promising biomarker for DKD and its distinct phenotypes in Chinese population.
... As a metabolite of hemoglobin, bilirubin functions as an effective antioxidant, protecting cells against damage from oxidative stress through interactions with the aforementioned processes (8)(9)(10). Briefly, bilirubin mitigates cellular damage of reactive oxygen species (ROS) by binding to ROS. ...
Background
Bilirubin has been widely reported to be a protective factor against diabetic kidney disease (DKD) in Asian populations. However, few large-sample analyses have been conducted in American populations. This study aimed to investigate the association between serum total bilirubin (STB) level and DKD in a US diabetic cohort.
Methods
This cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (NHANES) 2003–2018. Univariate and multivariate logistic regression analyses were performed to assess the association between STB level and DKD. Three models were conducted to control the potential confounding factors. Subgroup analysis was carried out for further validation.
Results
Among the 5,355 participants, the median age [interquartile range (IQR)] was 62 [52–71] years; 2,836 (52.96%) were male, and 1,576 (29.43%) were diagnosed with DKD. In the entire cohort, no significant association between STB level and DKD was observed in any logistic regression models ( p > 0.05). Subgroup analysis revealed that, in U.S. diabetic males, STB levels > 11.98 µmol/L were associated with a nearly 30% lower risk of DKD than STB levels ≤ 8.55 µmol/L. Additionally, a moderate STB level (8.56–11.98 μmol/L) was found associated with a nearly 25% lower risk of DKD in U.S. diabetic patients over 65 years old.
Conclusion
The association of STB level with DKD may depict differences across diverse populations, among which the impact of race, sex, and age requires thorough consideration and relevant inferences should be interpreted cautiously.
... It has also been shown that, along with antioxidant ability, bilirubin has other important biological properties, which include anti-inflammatory, immunomodulatory, cytoprotective and neuroprotective activities [130][131][132][133][134]. factor in endothelial function and determines the physiological redox homeostasis of the vascular endothelium [129]. ...
... It has also been shown that, along with antioxidant ability, bilirubin has other important biological properties, which include anti-inflammatory, immunomodulatory, cytoprotective and neuroprotective activities [130][131][132][133][134]. The scheme of bilirubin production from heme-containing molecules is shown in Figure 6a. ...
The use of conventional contrast media for diagnostic purposes (in particular, Gd-containing and iodinated agents) causes a large number of complications, the most common of which is contrast-induced nephropathy. It has been shown that after exposure to contrast agents, oxidative stress often occurs in patients, especially in people suffering from various diseases. Antioxidants in the human body can diminish the pathological consequences of the use of contrast media by suppressing oxidative stress. This review considers the research studies on the role of antioxidants in preventing the negative consequences of the use of contrast agents in diagnostics (mainly contrast-induced nephropathy) and the clinical trials of different antioxidant drugs against contrast-induced nephropathy. Composite antioxidant/contrast systems as theranostic agents are also considered.
... Bilirubin is produced by the breakdown of heme, a component derived from the haemoglobin of red blood cells or other haemoproteins, such as myoglobin, cytochromes and catalase. Heme oxygenase (HO), a rate-limiting enzyme in heme catabolism, cleaves heme to form biliverdin, which is subsequently converted by biliverdin reductase into bilirubin (Ayer et al., 2016;Tsai and Tarng, 2018). The change in bilirubin levels suggests liver cell damage (Singh et al., 2022). ...
Imidacloprid, a systemic neonicotinoid insecticide widely used across the world, has been discovered in numerous freshwater bodies. There are vast information available on the effects of imidacloprid on freshwater fish. This study further assessed the effects of acute doses (0, 10, 30, 50 and 70 mg/L) of imidacloprid on behaviour, swimming, hepatic and thyroid parameters of African catfish (Clarias gariepinus) after 96 hours exposure. Imidacloprid caused significant behavioural alterations (gulping, abnormal surface distribution, under-reactivity, hypoactivity, reduced opercula activity and loss of buoyancy) in the fish. Reduction in swimming speed and distance travelled was observed in fish exposed to imidacloprid. The levels of amylase significantly increased, while alterations were also recorded in the levels of hepatic (ALT, AST, total and conjugate bilirubin and lipase) and thyroid (T3, T4 and TSH) biomarkers. The findings showed that imidacloprid has the potential to harm aquatic species, justifying restrictions on the use of imidacloprid-based pesticides especially near aquatic habitats.
... In our study we found that specific T cell immunity response to SARS-CoV-2 inactivated vaccine in KTRs was negatively associated with blood unconjugated bilirubin, which is a test for hepatic function 49 . Apart from indicating liver dysfunction, unconjugated bilirubin in physiological ranges can function as an immunosuppressant, by impairment of antigen presentation in macrophages and inhibition of CD 4+ T cell responses, especially Th1 response (IL-2 and IFN-γ) [50][51][52] . These mechanisms may explain the lower protective T cell immunity response to SARS-CoV-2 in KTRs following vaccination in those with elevated unconjugated bilirubin. ...
The immunogenicity of SARS-CoV-2 vaccines is poor in kidney transplant recipients (KTRs). The factors related to poor immunogenicity to vaccination in KTRs are not well defined. Here, observational study demonstrated no severe adverse effects were observed in KTRs and healthy participants (HPs) after first or second dose of SARS-CoV-2 inactivated vaccine. Different from HPs with excellent immunity against SARS-CoV-2, IgG antibodies against S1 subunit of spike protein, receptor-binding domain, and nucleocapsid protein were not effectively induced in a majority of KTRs after the second dose of inactivated vaccine. Specific T cell immunity response was detectable in 40% KTRs after the second dose of inactivated vaccine. KTRs who developed specific T cell immunity were more likely to be female, and have lower levels of total bilirubin, unconjugated bilirubin, and blood tacrolimus concentrations. Multivariate logistic regression analysis found that blood unconjugated bilirubin and tacrolimus concentration were significantly negatively associated with SARS-CoV-2 specific T cell immunity response in KTRs. Altogether, these data suggest compared to humoral immunity, SARS-CoV-2 specific T cell immunity response are more likely to be induced in KTRs after administration of inactivated vaccine. Reduction of unconjugated bilirubin and tacrolimus concentration might benefit specific cellular immunity response in KTRs following vaccination.
... Globally, chronic kidney disease (CKD) is increasing and is associated with a higher risk of premature death [1], which is characterized by oxidative stress, vascular inflammation, and endothelial dysfunction [2]. Despite advances in medical treatment over the previous decades, clinical outcomes in patients with severe CKD, particularly those with end-stage renal disease (ESRD), have not significantly improved [3]. ...
... The level of oxidative damage is most prevalent in patients with ESRD [57]. This may lead to an increase in free radical generation, a loss in defenses against antioxidants, or both [1]. The primary mechanism implicated in CsA-induced kidney damage includes altered redox homeostasis [11]. ...
Cyclosporine A (CSA) is an immunosuppressive drug that has improved transplant survival rates. However, its use is often limited because it is thought to be linked to the development of chronic kidney disease after kidney transplants. This study aimed to investigate the protective effects and underlying mechanisms of physiological unconjugated (UC) hyperbilirubinemia mediated by UGT1A1 antisense oligonucleotide in a mouse model of CsA-induced chronic kidney disease, and match these with that of chitosan (CH) as a natural chelator against kidney injury. In the current study, CsA-treated mice were given an intravenous injection of UGT1A1 antisense morpholino oligonucleotide (16 µg/kg) every third day for 14 days. In serum samples, bilirubin, creatinine, and urea were determined. Markers of oxidative stress, antioxidant activities, and mRNA expression of target genes PPAR-α, cFn, eNOS, NF-B, AT1-R, ETA-R, Kim-1, and NGAL were measured in the kidney tissues. Moreover, histopathological examinations were carried out on the kidney tissue. Physiological UC hyperbilirubinemia could be a promising protective strategy against CsA-induced kidney disease in transplant recipients. UGT1A1 antisense oligonucleotide-induced physiological UC hyperbilirubinemia serum significantly protected against CsA-induced kidney dysfunction. UCB acts as a signaling molecule that protects against kidney disease through different mechanisms, including antioxidant, anti-inflammatory, and hormonal action, by activating nuclear hormone receptors (PPAR-α). Moreover, it significantly downregulated mRNA expression of NF-kB, ETA-R, iNOS, AT1-R, cFn, Kim-1, and NGAL in the kidney tissue and alleviated CsA-induced kidney histological changes in CsA-treated mice.
... This suggested that decreased serum bilirubin levels may reflect increased levels of oxidative stress and decreased levels of antioxidants, so bilirubin was considered to have strong antioxidant properties. Previous studies also have shown that bilirubin levels were negatively correlated with inflammatory status [28]. ...
Patients with end‐stage renal disease (ESRD) have significantly lower survival rates compared with the general population of the same age. Peritoneal dialysis (PD) is an effective treatment for patients with ESRD, but the clinical outcome of PD patients is still not promising. The survival of PD patients is associated with various clinical factors, and exploring some valid risk predictors may be beneficial for this population. In this review, by integrating the latest research, we summarized the association of some common and novel liver function parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma‐glutamyl transpeptidase (GGT), serum bilirubin, pre‐albumin, albumin, albumin‐globulin ratio (AGR), serum ferritin, and hyaluronic acid) with clinical outcomes in PD patients. It may contribute to a better understanding of potential risk factors and help to develop strategies to prevent the disease progression. This article is protected by copyright. All rights reserved.
