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Gao F, Guan C, Cheng N, Liu Y, Wu Y, Shi B, Huang J, Li S, Tong Y, Gao Y, Liu J, Wang C, Zhang C. Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on open-ring steroid scaffold. Eur J Med Chem 2025; 286:117250. [PMID: 39827488 DOI: 10.1016/j.ejmech.2025.117250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/05/2025] [Accepted: 01/05/2025] [Indexed: 01/22/2025]
Abstract
Vitamin D receptor (VDR) has emerged as a crucial target for the treatment of hepatic fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) components leading to impaired liver function. Activation of VDR has been shown to inhibit the transformation of hepatic stellate cells (HSCs), which play a key role in the development of liver fibrosis, thus reducing ECM production. In this study, a series of 37 non-steroidal VDR agonists with novel scaffold were designed and synthesized utilizing the scaffold hopping strategy. Over one-third of these compounds demonstrated significant VDR affinity and agonistic activity. Among them, compound E15 exhibited the highest VDR agonistic activity, showing promising results in vitro by effectively inhibiting HSC activation. Further in vivo assessments of E15 in a carbon tetrachloride-induced murine model of liver fibrosis demonstrated significant anti-fibrotic activity. Histological analyses revealed a reduction in lesions, inflammatory cell infiltration, and collagen deposition. Concurrently, blood biochemical assays indicated decreased hepatic fibrosis markers and improved serum liver function indices. Notably, E15 achieved these therapeutic effects without inducing hypercalcemia, a common adverse effect associated with VDR agonists such as calcipotriol. These findings underscore the potential of E15 as a potent and safe therapeutic agent for the treatment of liver fibrosis.
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Affiliation(s)
- Fei Gao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Chun Guan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Nuo Cheng
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yichen Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yue Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Bingyue Shi
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Jiayi Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Sitong Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yu Tong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yi Gao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Jiayi Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Cong Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China.
| | - Can Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China.
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Shahrebabak MG, Nezhad NZ, Azadmanesh MA, Shahpar A, Shahrebabak AG. Descriptive analysis of common causes of upper gastrointestinal bleeding in pediatric patients in Kerman: a study from 2022 to 2023. BMC Gastroenterol 2025; 25:152. [PMID: 40065200 PMCID: PMC11895127 DOI: 10.1186/s12876-025-03750-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Upper gastrointestinal bleeding (UGIB) in pediatric patients is a significant clinical concern requiring prompt diagnosis and management. This study aims to provide a descriptive analysis of the common causes of UGIB in pediatric patients in Kerman, Iran. METHODS A cross-sectional study was conducted at Afzalipour Hospital, Kerman, from January 2022 to December 2023. All pediatric patients under 18 years with UGIB were included. Data on demographics, clinical presentation, and endoscopic findings were collected and analyzed. RESULTS A total of 120 patients were included, with a mean age of 8.8 ± 4.7 years. Hematemesis was the predominant presenting feature (57.5%). All patients underwent endoscopy, with a diagnostic yield of 88.4%. Gastric erosion was the most common cause of UGIB (33.3%), followed by esophageal varices (13.3%). The etiology varied across age groups, with Mallory-Weiss syndrome being the second most common cause in infants. Blood transfusion was required in 31.67% of patients. CONCLUSION This study highlights the common causes and clinical features of pediatric UGIB in Kerman, Iran. Gastric erosion (33.3%) was the most frequent cause, and endoscopy achieved a high diagnostic yield (88.4%). Blood transfusion was necessary in 31.67% of patients. These findings emphasize the need for age-specific diagnostic strategies and reflect regional differences in UGIB etiology.
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Affiliation(s)
- Maryam Gholami Shahrebabak
- Department of Pediatrics, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Nazanin Zeinali Nezhad
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | | | - Amirhossein Shahpar
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman, Iran
| | - Azam Gholami Shahrebabak
- Department of Pediatrics Afzalipour Hospital, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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Wang P, Chen J, Li Z, Xiong H, Lei Z, Chen D, Zhang Y, Gao Z, Mo Z. Association of vitamin D with functional cure in chronic hepatitis B: Insights from a retrospective cohort study and an intervention study. Clin Nutr ESPEN 2024; 64:244-252. [PMID: 39423925 DOI: 10.1016/j.clnesp.2024.10.145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 09/19/2024] [Accepted: 10/13/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND & AIM Functional cure for chronic hepatitis B (CHB) patients can be achieved using nucleos(t)ide analogues (NAs) and pegylated interferon alpha (Peg-IFNα) combination treatment. However, the role of vitamin D in functional cure remains unclear. We aimed to investigate the association between vitamin D levels and functional cure in CHB patients. METHODS A retrospective study was conducted to detect changes in serum 25-hydroxyvitamin D (25(OH)D) levels in 526 CHB patients. Furthermore, an intervention study was conducted on 90 CHB patients with baseline vitamin D insufficiency, and 45 patients were randomly assigned to the control group receiving NAs/Peg-IFNα treatment, whereas the remaining patients were categorized into the vitamin D group (VD group) receiving NAs/Peg-IFNα treatment combined with vitamin D supplementation at 800 IU/day. RESULTS A retrospective study revealed a progressive elevation in serum 25(OH)D levels throughout the duration of treatment. The cured group displayed significantly higher serum 25(OH)D levels than the uncured group (P = 0.046) at the end of treatment, and the changes in serum 25(OH)D (Δ25(OH)D) levels between the two groups were found to be significantly different (P < 0.0001). In the intervention study, the VD group tended to have an increased functional cure rate (48.0 %) compared with the control group (34.3 %) in the binary logistic regression equation analysis (P = 0.09). Notably, a linear mixed-effects model in the longitudinal analysis indicated a significant impact of serum 25(OH)D levels on treatment outcomes (P = 0.017). CONCLUSIONS Serum 25(OH)D and Δ25(OH)D were both positively associated with functional cure in this retrospective study, and vitamin D supplementation may be helpful for functional cure in CHB patients. REGISTRATION NUMBER OF CLINICAL TRIAL ChiCTR1800020108.
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Affiliation(s)
- Peipei Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China
| | - Junjian Chen
- Institute of Human Virology, Zhongshan School of Medicine (Sun Yat-sen University), No. 74, Zhong Shan II Rd, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China
| | - Zhipeng Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China
| | - Husheng Xiong
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Ziying Lei
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China
| | - Dabiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China
| | - Ying Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China.
| | - Zhiliang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China.
| | - Zhishuo Mo
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China.
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Rastegar-Moghaddam SH, Akbarian M, Rajabian A, Alipour F, Hojjati Shargh A, Masoomi R, Ebrahimzadeh Bideskan A, Hosseini M. Potential therapeutic impacts of vitamin D on hypothyroid-induced heart and kidney fibrosis and oxidative status in male rat. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024:10.1007/s00210-024-03593-8. [PMID: 39535596 DOI: 10.1007/s00210-024-03593-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
There are several interactions between thyroid hormones (THs) and kidney and heart function. Consequently, THs deficit results in profound changes in renal and cardiac function regulation. Interestingly, emerging evidence suggests that vitamin D (Vit D) may benefit to fibrotic lesions in various tissues. Herein, this study was designed to investigate the potential impact of Vit D on renal and cardiac fibrosis in hypothyroid rats. Forty male Wistar rats were divided into four groups as follow: control, hypothyroid (0.05% PTU in drinking water), and hypothyroid + Vit D (PTU and doses of 100 or 500 IU/kg/day, by gavage) groups. After 6 weeks, biochemical parameters such as creatinine and urea in serum samples, and oxidative stress markers including malondialdehyde (MDA), total thiol groups, and superoxide dismutase (SOD) in renal and cardiac tissues homogenate were measured. Also, renal and cardiac fibrosis was evaluated histologically using Masson's trichrome staining. Hypothyroidism significantly increased creatinine and urea. Also, in hypothyroid group renal and cardiac fibrosis as well as MDA were increased, while anti-oxidative markers including total thiol group and SOD were decreased. Administration of Vit D significantly improved these alterations in oxidative stress markers and fibrosis in renal and cardiac tissues. In conclusion, this study highlighted that Vit D supplementation reduced renal and cardiac fibrosis and improved oxidative stress. These results support the emerging experimental findings linking Vit D being introduced as a potential therapeutic agent.
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Affiliation(s)
| | - Mahsan Akbarian
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arezoo Rajabian
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Alipour
- Department of Anatomy and Cell Biology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Reza Masoomi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Ebrahimzadeh Bideskan
- Department of Anatomy and Cell Biology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Hosseini
- Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Derogar Kasmaei SR, Parastouei K, Hosseini Ahangar B, Saberifiroozi M, Taghdir M. Effects of vitamin D supplementation on the glycaemic indices, lipid profile and liver function tests in patients with cirrhosis: a double-blind randomised controlled trial. BMJ Nutr Prev Health 2024; 7:e000938. [PMID: 39882304 PMCID: PMC11773653 DOI: 10.1136/bmjnph-2024-000938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 08/09/2024] [Indexed: 01/31/2025] Open
Abstract
Background Liver cirrhosis is considered a progressive disease that can eventually result in death. Vitamin D deficiency is prevalent in patients with cirrhosis. Few studies have been conducted on the effect of vitamin D supplementation in patients with cirrhosis. Objectives The aim of this study was to identify the effect of vitamin D supplementation on lipid profile, glycaemic indices and liver function tests in patients with cirrhosis. Methods Sixty patients with cirrhosis were involved in this double-blind, randomised controlled clinical trial. During the intervention, patients received one 50 000 IU pearl of vitamin D supplement or placebo per week for 12 weeks. Before and after supplementation, we assessed serum 25-hydroxy-vitamin-D3 (25(OH) D3), glycaemic indices (insulin, haemoglobin A1c, fasting blood glucose (FBG) and homeostatic model assessment for insulin resistance (HOMA-IR)), lipid profile and liver function tests. Results Baseline variables were not significantly different between groups. The present study indicated that over the 12 weeks, vitamin D supplementation significantly increased serum 25(OH) D3 (p<0.001), and also significantly decreased FBG (p=0.006), and HOMA-IR (p=0.001). Conclusions Vitamin D supplementation significantly improves FBG and HOMA-IR as well as serum 25(OH) D3 in patients with cirrhosis. Trial registration number The protocol of the study was registered at the Iranian Registry of Clinical Trials (IRCT) (IRCT20140502017522N2).
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Affiliation(s)
| | - Karim Parastouei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Behnam Hosseini Ahangar
- Baqiyatallah Research Center for Gastroenterology and Liver Disease (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehdi Saberifiroozi
- Liver and Pancreatobiliary Disease Research Center (LPDRC), Digestive Disease Research Institute, Tehran University of Medical Science, Tehran, Iran
| | - Maryam Taghdir
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
- Department of Nutrition and Food Hygiene - Faculty of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Fang JX, Han Y, Meng J, Zou HM, Hu X, Han YX, Huang F, Gu Q, Wang SJ. Relationship between non-alcoholic fatty liver and progressive fibrosis and serum 25-hydroxy vitamin D in patients with type 2 diabetes mellitus. BMC Endocr Disord 2024; 24:108. [PMID: 38982394 PMCID: PMC11234559 DOI: 10.1186/s12902-024-01640-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/02/2024] [Indexed: 07/11/2024] Open
Abstract
OBJECTIVE We aimed to analyze the relationship between non-alcoholic fatty liver and progressive fibrosis and serum 25-hydroxy vitamin D (25(OH)D) in patients with type 2 diabetes mellitus. METHODS A total of 184 patients with T2DM who were hospitalized in the Department of Endocrinology of the ShiDong Clinical Hospital between January 2023 and June 2023 were selected. We compared review of anthropometric, biochemical, and inflammatory parameters and non-invasive scores between groups defined by ultrasound NAFLD severity grades.We determine the correlation between 25(OH)D and FLI and FIB-4 scores, respectively. RESULTS Statistically significant differences were seen between BMI, WC, C-peptide levels, FPG, ALT, serum 25(OH)D, TC, HDL, lumbar spine bone density, FLI, and FIB-4 in different degrees of NAFLD. Multivariate logistic regression analysis showed that 25(OH)D (OR = 1.26, p = 0.001), age (OR = 0.93, P < 0.001) and BMI (OR = 1.04, p = 0.007) were independent predictors of NAFLD in patients with T2DM. CONCLUSIONS This study revealed the correlation between serum 25(OH)D levels and NAFLD in patients with T2DM. We also demonstrated that serum 25(OH)D levels were negatively correlated with FLI/FIB-4 levels in patients with T2DM with NAFLD, suggesting that vitamin D deficiency may promote hepatic fibrosis progression in T2DM with NAFLD.
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Affiliation(s)
- Jing-Xian Fang
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Yu Han
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Jian Meng
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Hui-Ming Zou
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Xue Hu
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Yue-Xia Han
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Fang Huang
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Qing Gu
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China.
| | - Sui-Jun Wang
- Endocrinology and Metabolism, Yangpu District Shidong Hospital of Shanghai, No.999, Shiguang Road, Yangpu District, Shanghai, 200438, China.
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Aggeletopoulou I, Tsounis EP, Triantos C. Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights. Int J Mol Sci 2024; 25:4901. [PMID: 38732118 PMCID: PMC11084591 DOI: 10.3390/ijms25094901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.
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Affiliation(s)
| | | | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
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Ioniuc I, Lupu A, Tarnita I, Mastaleru A, Trandafir LM, Lupu VV, Starcea IM, Alecsa M, Morariu ID, Salaru DL, Azoicai A. Insights into the Management of Chronic Hepatitis in Children-From Oxidative Stress to Antioxidant Therapy. Int J Mol Sci 2024; 25:3908. [PMID: 38612717 PMCID: PMC11011982 DOI: 10.3390/ijms25073908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/22/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Recent research has generated awareness of the existence of various pathophysiological pathways that contribute to the development of chronic diseases; thus, pro-oxidative factors have been accepted as significant contributors to the emergence of a wide range of diseases, from inflammatory to malignant. Redox homeostasis is especially crucial in liver pathology, as disturbances at this level have been linked to a variety of chronic diseases. Hepatitis is an umbrella term used to describe liver inflammation, which is the foundation of this disease regardless of its cause. Chronic hepatitis produces both oxidative stress generated by hepatocyte inflammation and viral inoculation. The majority of hepatitis in children is caused by a virus, and current studies reveal that 60-80% of cases become chronic, with many young patients still at risk of advancing liver damage. This review intends to emphasize the relevance of understanding these pathological redox pathways, as well as the need to update therapeutic strategies in chronic liver pathology, considering the beneficial effects of antioxidants.
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Affiliation(s)
- Ileana Ioniuc
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
| | - Ancuta Lupu
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
| | - Irina Tarnita
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
| | - Alexandra Mastaleru
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.M.); (D.L.S.)
| | - Laura Mihaela Trandafir
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
| | - Vasile Valeriu Lupu
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
| | - Iuliana Magdalena Starcea
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
| | - Mirabela Alecsa
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
| | - Ionela Daniela Morariu
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Delia Lidia Salaru
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.M.); (D.L.S.)
| | - Alice Azoicai
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.I.); (I.T.); (L.M.T.); (I.M.S.); (M.A.); (A.A.)
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Tourkochristou E, Mouzaki A, Triantos C. Gene Polymorphisms and Biological Effects of Vitamin D Receptor on Nonalcoholic Fatty Liver Disease Development and Progression. Int J Mol Sci 2023; 24:ijms24098288. [PMID: 37175993 PMCID: PMC10179740 DOI: 10.3390/ijms24098288] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/28/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with increasing prevalence worldwide. The genetic and molecular background of NAFLD pathogenesis is not yet clear. The vitamin D/vitamin D receptor (VDR) axis is significantly associated with the development and progression of NAFLD. Gene polymorphisms may influence the regulation of the VDR gene, although their biological significance remains to be elucidated. VDR gene polymorphisms are associated with the presence and severity of NAFLD, as they may influence the regulation of adipose tissue activity, fibrosis, and hepatocellular carcinoma (HCC) development. Vitamin D binds to the hepatic VDR to exert its biological functions, either by activating VDR transcriptional activity to regulate gene expression associated with inflammation and fibrosis or by inducing intracellular signal transduction through VDR-mediated activation of Ca2+ channels. VDR activity has protective and detrimental effects on hepatic steatosis, a characteristic feature of NAFLD. Vitamin D-VDR signaling may control the progression of NAFLD by regulating immune responses, lipotoxicity, and fibrogenesis. Elucidation of the genetic and molecular background of VDR in the pathophysiology of NAFLD will provide new therapeutic targets for this disease through the development of VDR agonists, which already showed promising results in vivo.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Rion, 26504 Patras, Greece
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Rion, 26504 Patras, Greece
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Abouzid M, Karaźniewicz-Łada M, Abdelazeem B, Brašić JR. Research Trends of Vitamin D Metabolism Gene Polymorphisms Based on a Bibliometric Investigation. Genes (Basel) 2023; 14:215. [PMID: 36672957 PMCID: PMC9859253 DOI: 10.3390/genes14010215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/05/2023] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
Vitamin D requires activation to show its pharmacological effect. While most studies investigate the association between vitamin D and disease, only a few focus on the impact of vitamin D metabolism gene polymorphisms (vitDMGPs). This bibliometric study aims to provide an overview of current publications on vitDMGPs (CYP27B1, CYP24A1, CYP2R1, CYP27A1, CYP2R1, DHCR7/NADSYN1), compare them across countries, affiliations, and journals, and inspect keywords, co-citations, and citation bursts to identify trends in this research field. CiteSpace© (version 6.1.R3, Chaomei Chen), Bibliometrix© (R version 4.1.3 library, K-Synth Srl, University of Naples Federico II, Naples, Italy), VOSviewer© (version 1.6.1, Nees Jan van Eck and Ludo Waltman, Leiden University, Leiden, Netherlands) and Microsoft® Excel 365 (Microsoft, Redmond, Washington, USA) classified and summarized Web of Science articles from 1998 to November 2022. We analyzed 2496 articles and built a timeline of co-citations and a bibliometric keywords co-occurrence map. The annual growth rate of vitDMGPs publications was 18.68%, and their relative research interest and published papers were increasing. The United States of America leads vitDMGPs research. The University of California System attained the highest quality of vitDMGPs research, followed by the American National Institutes of Health and Harvard University. The three productive journals on vitDMGPs papers are J. Steroid. Biochem. Mol. Biol., PLOS ONE, and J. Clin. Endocrinol. Metab. We highlighted that the vitDMGPs domain is relatively new, and many novel research opportunities are available, especially those related to studying single nucleotide polymorphisms or markers in a specific gene in the vitamin D metabolism cycle and their association with disease. Genome-wide association studies, genetic variants of vitDMGPs, and vitamin D and its role in cancer risk were the most popular studies. CYP24A1 and CYB27A1 were the most-studied genes in vitDMGPs. Insulin was the longest-trending studied hormone associated with vitDMGPs. Trending topics in this field relate to bile acid metabolism, transcriptome and gene expression, biomarkers, single nucleotide polymorphism, and fibroblast growth factor 23. We also expect an increase in original research papers investigating the association between vitDMGPs and coronavirus disease 2019, hypercalcemia, Smith-Lemli-Opitz syndrome, 27-hydroxycholesterol, and mendelian randomization. These findings will provide the foundations for innovations in the diagnosis and treatment of a vast spectrum of conditions.
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Affiliation(s)
- Mohamed Abouzid
- Department of Physical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3 St., 60-806 Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Marta Karaźniewicz-Łada
- Department of Physical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3 St., 60-806 Poznan, Poland
| | - Basel Abdelazeem
- Department of Internal Medicine, McLaren Health Care, Flint, MI 48532, USA
- Department of Internal Medicine, Michigan State University, East Lansing, MI 48823, USA
| | - James Robert Brašić
- Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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11
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Eitah HE, Attia HN, Soliman AAF, Gamal El Din AA, Mahmoud K, Sayed RH, Maklad YA, El-Sahar AE. Vitamin D ameliorates diethylnitrosamine-induced liver preneoplasia: A pivotal role of CYP3A4/CYP2E1 via DPP-4 enzyme inhibition. Toxicol Appl Pharmacol 2023; 458:116324. [PMID: 36442531 DOI: 10.1016/j.taap.2022.116324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 11/11/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
Abstract
Growing evidence has indicated that vitamin D (Vit D) regulates cell proliferation and differentiation in cancer cells. Accordingly, the present study was conducted to investigate the possible beneficial effects of Vit D on diethylnitrosamine (DEN)-induced liver preneoplasia. The effect of Vit D on HepG2 cells was investigated using MTT assay. Additionally, liver preneoplasia was induced in Swiss male albino mice by giving overnight fasted animals 5 consecutive doses of DEN (75 mg/kg/week). Oral treatment with Vit D (200 IU/kg/day) was initiated either 2 weeks before DEN (first protocol) or 1 week after the first dose of DEN injection (second protocol). At the end of the experiment, tissue levels of GGT, DPP-4, TNF-α, IL-6, CYP2E1, and CYP3A4 were also estimated. Moreover, the histopathological study of liver tissue and immunohistochemical detection of GST-P, PCNA, and NF-κB were performed. Vit D exerted a significant cytotoxic effect on HepG2 cells via significantly increasing BAX, p53, and BAX/Bcl2 ratio, and significantly decreasing Bcl2 mRNA expression. In both in vivo protocols, Vit D was capable of normalizing relative liver weight, PCNA, altered hepatocellular foci, and ductular proliferation. Moreover, Vit D significantly reduced the DEN-induced elevation of AST, ALT, ALP, GGT, DDP-4, TNF-α, IL-6, CYP2E1, liver DNA damage, GST-P, NF-κB, nuclear hyperchromasia/pleomorphism, cholestasis, and inflammatory cell aggregates, but significantly increased CYP3A4 content. In conculsion, current results reflect the potential impact of Vit D in the management of early stages of liver cancer.
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Affiliation(s)
- Hebatollah E Eitah
- Medicinal and Pharmaceutical Chemistry Department, Pharmacology Group, National Research Centre, Dokki, Giza, Egypt
| | - Hanan Naeim Attia
- Medicinal and Pharmaceutical Chemistry Department, Pharmacology Group, National Research Centre, Dokki, Giza, Egypt
| | - Ahmed A F Soliman
- Pharmacognosy Department, National Research Centre, Dokki, Giza, Egypt
| | | | - Khaled Mahmoud
- Pharmacognosy Department, National Research Centre, Dokki, Giza, Egypt
| | - Rabab H Sayed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Yousreya A Maklad
- Medicinal and Pharmaceutical Chemistry Department, Pharmacology Group, National Research Centre, Dokki, Giza, Egypt
| | - Ayman E El-Sahar
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; School of Pharmacy, Newgiza University, Cairo, Egypt
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Pop TL, Sîrbe C, Benţa G, Mititelu A, Grama A. The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases. Int J Mol Sci 2022; 23:ijms231810705. [PMID: 36142636 PMCID: PMC9503777 DOI: 10.3390/ijms231810705] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/09/2022] [Accepted: 09/12/2022] [Indexed: 11/24/2022] Open
Abstract
Vitamin D (calciferol) is a fat-soluble vitamin that has a significant role in phospho-calcium metabolism, maintaining normal calcium levels and bone health development. The most important compounds of vitamin D are cholecalciferol (vitamin D3, or VD3) and ergocalciferol (vitamin D2, or VD2). Besides its major role in maintaining an adequate level of calcium and phosphate concentrations, vitamin D is involved in cell growth and differentiation and immune function. Recently, the association between vitamin D deficiency and the progression of fibrosis in chronic liver disease (CLD) was confirmed, given the hepatic activation process and high prevalence of vitamin D deficiency in these diseases. There are reports of vitamin D deficiency in CLD regardless of the etiology (chronic viral hepatitis, alcoholic cirrhosis, non-alcoholic fatty liver disease, primary biliary cirrhosis, or autoimmune hepatitis). Vitamin D binding protein (VDBP) is synthesized by the liver and has the role of binding and transporting vitamin D and its metabolites to the target organs. VDBP also plays an important role in inflammatory response secondary to tissue damage, being involved in the degradation of actin. As intense research during the last decades revealed the possible role of vitamin D in liver diseases, a deeper understanding of the vitamin D, vitamin D receptors (VDRs), and VDBP involvement in liver inflammation and fibrogenesis could represent the basis for the development of new strategies for diagnosis, prognosis, and treatment of liver diseases. This narrative review presents an overview of the evidence of the role of vitamin D and VDBP in CLD, both at the experimental and clinical levels.
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Affiliation(s)
- Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Claudia Sîrbe
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence:
| | - Gabriel Benţa
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Alexandra Mititelu
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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Ravaioli F, Pivetti A, Di Marco L, Chrysanthi C, Frassanito G, Pambianco M, Sicuro C, Gualandi N, Guasconi T, Pecchini M, Colecchia A. Role of Vitamin D in Liver Disease and Complications of Advanced Chronic Liver Disease. Int J Mol Sci 2022; 23:ijms23169016. [PMID: 36012285 PMCID: PMC9409132 DOI: 10.3390/ijms23169016] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 12/12/2022] Open
Abstract
Vitamin D is a crucial nutrient with many pleiotropic effects on health and various chronic diseases. The purpose of this review is to provide a detailed report on the pathophysiological mechanisms underlying vitamin D deficiency in patients with chronic liver disease, addressing the different liver etiologies and the condition of advanced chronic liver disease (cirrhosis) with related complications. To date, patients with liver disease, regardless of underlying etiology, have been shown to have reduced levels of vitamin D. There is also evidence of the predictive role of vitamin D values in complications and progression of advanced disease. However, specific indications of vitamin D supplementation are not conclusive concerning what is already recommended in the general population. Future studies should make an effort to unify and validate the role of vitamin D supplementation in chronic liver disease.
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Affiliation(s)
- Federico Ravaioli
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40128 Bologna, Italy
- Correspondence:
| | - Alessandra Pivetti
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Lorenza Di Marco
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Christou Chrysanthi
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Gabriella Frassanito
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Martina Pambianco
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Chiara Sicuro
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Noemi Gualandi
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Tomas Guasconi
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Maddalena Pecchini
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
| | - Antonio Colecchia
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy
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14
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Aggeletopoulou I, Thomopoulos K, Mouzaki A, Triantos C. Vitamin D–VDR Novel Anti-Inflammatory Molecules—New Insights into Their Effects on Liver Diseases. Int J Mol Sci 2022; 23:ijms23158465. [PMID: 35955597 PMCID: PMC9369388 DOI: 10.3390/ijms23158465] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 02/05/2023] Open
Abstract
There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D–VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D–VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
- Correspondence:
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
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15
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Vitamin D, liver-related biomarkers, and distribution of fat and lean mass in young patients with Fontan circulation. Cardiol Young 2022; 32:861-868. [PMID: 34338624 DOI: 10.1017/s1047951121003115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION/AIM Young patients with Fontan circulation may have low serum 25-hydroxyvitamin D levels, an affected liver, and unhealthy body compositions. This study aimed to explore the association between vitamin D intake/levels, liver biomarkers, and body composition in young Fontan patients. METHOD We collected prospective data in 2017 to 2018, obtained with food-frequency questionnaires, biochemical analyses of liver biomarkers, and dual-energy X-ray absorptiometry scans in 44 children with Fontan circulation. Body compositions were compared to matched controls (n = 38). Linear regression analyses were used to investigate associations of biomarkers, leg pain, and lean mass on serum levels of 25-hydroxyvitamin D. Biomarkers were converted to z scores and differences were evaluated within the Fontan patients. RESULTS Our Fontan patients had a daily mean vitamin D intake of 9.9 µg and a mean serum 25-hydroxyvitamin D of 56 nmol/L. These factors were not associated with fat or lean mass, leg pain, or biomarkers of liver status. The Fontan patients had significantly less lean mass, but higher fat mass than controls. Male adolescents with Fontan circulation had a greater mean abdominal fat mass than male controls and higher cholesterol levels than females with Fontan circulation. CONCLUSION Vitamin D intake and serum levels were not associated with body composition or liver biomarkers in the Fontan group, but the Fontan group had lower lean mass and higher fat mass than controls. The more pronounced abdominal fat mass in male adolescents with Fontan circulation might increase metabolic risks later in life.
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Celik S, Golbasi H, Gulucu S, Guclu M, Caliskan CS, Celik S, Akpak YK, Golbasi C. Role of Vitamin B12 and Vitamin D levels in intrahepatic cholestasis of pregnancy and correlation with total bile acid. J OBSTET GYNAECOL 2022; 42:1847-1852. [PMID: 35482784 DOI: 10.1080/01443615.2022.2042797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
This study aimed to evaluate the relationship between intrahepatic cholestasis of pregnancy (ICP) and Vitamin D and B12 levels. The study was a retrospective, cross-sectional, case-control study that evaluated 92 ICP cases and 102 pregnant women without any additional disease. ICP cases were grouped as mild and severe according to their total bile acid (TBA) levels, and their relationship with Vitamin D and B12 levels and perinatal outcomes was evaluated. Vitamin D and B12 levels of the ICP group were significantly lower than those of the control group. There was a moderate negative correlation between TBA and Vitamin D levels and a low negative correlation between TBA and Vitamin B12 levels. Adverse neonatal outcomes were significantly higher in the severe ICP group than in the mild ICP group. IMPACT STATEMENTWhat is already known on this subject? The pathophysiology of ICP, which can lead to adverse perinatal outcomes, is not yet fully understood, and there is no preventive treatment.What do the results of this study add? This study showed that Vitamins B12 and D levels were low in women with ICP and that TBA levels were negatively correlated with Vitamin D and B12 levels.What are the implications of these findings for clinical practice and/or further research? This study may guide future studies in terms of explaining the etiopathogenesis of ICP and developing treatment options.
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Affiliation(s)
- Sebahattin Celik
- Department of Obstetrics and Gynecology, Balikesir State Hospital, Balikesir, Turkey
| | - Hakan Golbasi
- Department of Obstetrics and Gynecology, Division of Perinatology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Selim Gulucu
- Department of Obstetrics and Gynecology, Gaziosmanpasa University, Tokat, Turkey
| | - Mehmet Guclu
- Department of Obstetrics and Gynecology, Marmara University, Pendik Training and Research Hospital, Istanbul, Turkey
| | - Canan Soyer Caliskan
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Samettin Celik
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Yasam Kemal Akpak
- Department of Obstetrics and Gynecology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Ceren Golbasi
- Department of Obstetrics and Gynecology, Tinaztepe University, Izmir, Turkey
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Mongy NNE, Hilal RF. How far is vitamin D implicated in cutaneous infections. Clin Dermatol 2021; 40:198-205. [PMID: 34893391 DOI: 10.1016/j.clindermatol.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Vitamin D is an important cornerstone in the immunologic cascade of many skin infections, systemic infections with cutaneous presentations, and other infectious dermatologic diseases where infections could be a culprit. Vitamin D supplementation is proposed as a protective measure against their occurrence and exacerbation, especially with the emergence of several viral pandemics in recent years. Vitamin D plays a key role in the maintenance of a balanced immunologic profile which could be reflected by a lowered incidence and morbidity of infections. Vitamin D screening and supplementation in patients with deficiencies or insufficiencies should be a part of the dermatologic approach to patients with these diseases.
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Affiliation(s)
- Naglaa Nabil El Mongy
- Professor of Dermatology, Kasr Al Ainy Teaching Hospital, Cairo University, Cairo, Egypt
| | - Rana Fathy Hilal
- Associate Professor of Dermatology, Kasr Al Ainy Teaching Hospital, Cairo University, Cairo, Egypt.
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18
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Sun S, Xu M, Zhuang P, Chen G, Dong K, Dong R, Zheng S. Effect and mechanism of vitamin D activation disorder on liver fibrosis in biliary atresia. Sci Rep 2021; 11:19883. [PMID: 34615940 PMCID: PMC8494743 DOI: 10.1038/s41598-021-99158-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
To investigate the mechanism of 25 hydroxyvitamin D (25(OH)D) deficiency in children with biliary atresia (BA) and its effect on liver fibrosis. The serum vitamin D and 25(OH)D, and expression of 25 hydroxylase (CYP2R1 and CYP27A1) in the liver of BA patients were detected and compared with those in the control group. We investigated the effect of differential expression of CYP2R1 in hepatocytes on the expression of genes related to liver fibrosis in primary hepatic stellate cells (HSCs) of BA and animal models of cholestasis. The ratio of 25(OH)D/vitamin D in the BA group was significantly lower than that in the control group. The mRNA and protein expression of CYP2R1 and CYP27A1 in liver tissue of the BA group was significantly lower than that in the control group. Exogenous active vitamin D (calcitriol) inhibited the proliferation and migration of primary HSCs isolated from BA patients, and reduced the expression of fibrosis-related genes in vitro. Downregulation of expression of CYP2R1 in hepatocytes increased expression of transforming growth factor (TGF)-β1, collagen (Col)-1α1 and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased the expression of matrix metalloproteinase (MMP)-2 in cocultured primary HSCs of BA. Upregulation of expression of CYP2R1 in mice with bile duct ligation significantly increased the level of 25(OH)D, decreased the expression of TGF-β1, Col-1α1 and TIMP-1, and increased the expression of MMP-2. Children with BA have impaired vitamin D activation due to CYP2R1 deficiency. The dysactivation of vitamin D can promote the proliferation and activation of HSCs and participate in the development of hepatic fibrosis in BA.
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Affiliation(s)
- Song Sun
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Menghua Xu
- The Center of Laboratory Medicine, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Peijun Zhuang
- Anesthesiology Department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Gong Chen
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Kuiran Dong
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Rui Dong
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
| | - Shan Zheng
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
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Ali ME, Halby HM, Ali MY, Hassan EA, El-Mokhtar MA, Sayed IM, Thabet MM, Fouad M, El-Ashmawy AM, Mahran ZG. Role of Serum Vitamin D, Interleukin 13, and microRNA-135a in Hepatocellular Carcinoma and Treatment Failure in Egyptian HCV-Infected Patients Receiving Direct Antiviral Agents. Viruses 2021; 13:2008. [PMID: 34696438 PMCID: PMC8539757 DOI: 10.3390/v13102008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/17/2021] [Accepted: 09/25/2021] [Indexed: 12/12/2022] Open
Abstract
Direct-acting antivirals (DAAs) are used for hepatitis C virus (HCV) treatment. However, treatment failure and hepatocellular carcinoma (HCC) development following treatment was reported. In this study, we assessed the role of serum vitamin D, interleukin 13 (IL-13), and microRNA-135a in the prediction of treatment failure with DAA and HCC development among Egyptian HCV-infected patients. A total of 950 patients with HCV-related chronic liver disease underwent DAA treatment. Before DAAs, serum vitamin D and IL-13 were determined by ELISA, and gene expression of miRNA-135a was assessed in serum by real-time PCR. The predictive abilities of these markers were determined using the receiver operating characteristic (ROC) curve. Sustained virological response (SVR) was achieved in 92.6% of HCV-infected patients (responders). High viral load, IL-13, miRNA-135a, and low vitamin D levels were associated with treatment failure and HCC development. HCC development was recorded in non-responders, but not in the responders (35.7% vs. 0% p < 0.001). In conclusion: serum IL-13, Vitamin D, and miRNA-135a could be potential biomarkers in monitoring DAA treatment and HCC prediction. DAAs-induced SVR may decrease the incidence of HCC.
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Affiliation(s)
- Mohamed E. Ali
- Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; (M.E.A.); (H.M.H.); (M.Y.A.)
| | - Hamada M. Halby
- Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; (M.E.A.); (H.M.H.); (M.Y.A.)
| | - Mamdouh Yones Ali
- Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; (M.E.A.); (H.M.H.); (M.Y.A.)
| | - Elham Ahmed Hassan
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut 71515, Egypt;
| | - Mohamed A. El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; (M.A.E.-M.); (I.M.S.)
| | - Ibrahim M. Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; (M.A.E.-M.); (I.M.S.)
| | - Marwa M. Thabet
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt;
| | - Magdy Fouad
- Hepato-Gastroenterology Unit, Tropical Medicine Department, Faculty of Medicine, El-Minia University, Minya 61519, Egypt;
| | - Ahmed M. El-Ashmawy
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut 71515, Egypt;
| | - Zainab Gaber Mahran
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut 71515, Egypt;
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Abdrabbo M, Birch CM, Brandt M, Cicigoi KA, Coffey SJ, Dolan CC, Dvorak H, Gehrke AC, Gerzema AEL, Hansen A, Henseler EJ, Huelsbeck AC, LaBerge B, Leavens CM, Le CN, Lindquist AC, Ludwig RK, Reynolds JH, Severson NJ, Sherman BA, Sillman HW, Smith MA, Smith MA, Snortheim MJ, Svaren LM, Vanderpas EC, Wackett MJ, Wozney AJ, Bhattacharyya S, Hati S. Vitamin D and COVID-19: A review on the role of vitamin D in preventing and reducing the severity of COVID-19 infection. Protein Sci 2021; 30:2206-2220. [PMID: 34558135 PMCID: PMC8521296 DOI: 10.1002/pro.4190] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/18/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022]
Abstract
Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) is a pathogenic coronavirus causing COVID‐19 infection. The interaction between the SARS‐CoV‐2 spike protein and the human receptor angiotensin‐converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide‐thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID‐19. However, the molecular‐level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID‐19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID‐19 infection or reducing the severity of the disease.
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Affiliation(s)
- Mobeen Abdrabbo
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Cole M Birch
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Michael Brandt
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Kelsey A Cicigoi
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Stephen J Coffey
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Connor C Dolan
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Hannah Dvorak
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Ava C Gehrke
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Audrey E L Gerzema
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Abby Hansen
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Ethan J Henseler
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Alyssa C Huelsbeck
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Ben LaBerge
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Caterra M Leavens
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Christine N Le
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Allison C Lindquist
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Rickaela K Ludwig
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Jacob H Reynolds
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Nathaniel J Severson
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Brandon A Sherman
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Hunter W Sillman
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Michael A Smith
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Macey A Smith
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Marissa J Snortheim
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Levi M Svaren
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Emily C Vanderpas
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Miles J Wackett
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Alec J Wozney
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Sudeep Bhattacharyya
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
| | - Sanchita Hati
- Department of Chemistry and Biochemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, USA
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21
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Bjelakovic M, Nikolova D, Bjelakovic G, Gluud C. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev 2021; 8:CD011564. [PMID: 34431511 PMCID: PMC8407054 DOI: 10.1002/14651858.cd011564.pub3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Vitamin D deficiency is often reported in people with chronic liver diseases. Improving vitamin D status could therefore be beneficial for people with chronic liver diseases. OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation in adults with chronic liver diseases. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and enquired experts and pharmaceutical companies as to additional trials. All searches were up to November 2020. SELECTION CRITERIA Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of evidence. MAIN RESULTS We included 27 randomised clinical trials with 1979 adult participants. This review update added 12 trials with 945 participants. We assessed all trials as at high risk of bias. All trials had a parallel-group design. Eleven trials were conducted in high-income countries and 16 trials in middle-income countries. Ten trials included participants with chronic hepatitis C, five trials participants with liver cirrhosis, 11 trials participants with non-alcoholic fatty liver disease, and one trial liver transplant recipients. All of the included trials reported the baseline vitamin D status of participants. Participants in nine trials had baseline serum 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), whilst participants in the remaining 18 trials were vitamin D insufficient (less than 20 ng/mL). Twenty-four trials administered vitamin D orally, two trials intramuscularly, and one trial intramuscularly and orally. In all 27 trials, the mean duration of vitamin D supplementation was 6 months, and the mean follow-up of participants from randomisation was 7 months. Twenty trials (1592 participants; 44% women; mean age 48 years) tested vitamin D3 (cholecalciferol); three trials (156 participants; 28% women; mean age 54 years) tested vitamin D2; four trials (291 participants; 60% women; mean age 52 years) tested 1,25-dihydroxyvitamin D; and one trial (18 participants; 0% women; mean age 52 years) tested 25-hydroxyvitamin D. One trial did not report the form of vitamin D. Twelve trials used a placebo, whilst the other 15 trials used no intervention in the control group. Fourteen trials appeared to be free of vested interest. Eleven trials did not provide any information on clinical trial support or sponsorship. Two trials were funded by industry. We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on all-cause mortality (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.51 to 1.45; 27 trials; 1979 participants). The mean follow-up was 7 months (range 1 to 18 months). We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) (follow-up: 12 months); serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial 20 participants); and non-serious adverse events. The certainty of evidence for all outcomes is very low. We found no data on liver-related morbidity such as gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, ascites, or liver cancer. There were also no data on health-related quality of life. The evidence is also very uncertain regarding the effect of vitamin D versus placebo or no intervention on rapid, early, and sustained virological response in people with chronic hepatitis C. AUTHORS' CONCLUSIONS Given the high risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, vitamin D supplementation versus placebo or no intervention may increase or reduce all-cause mortality, liver-related mortality, serious adverse events, or non-serious adverse events in adults with chronic liver diseases. There is a lack of data on liver-related morbidity and health-related quality of life. Further evidence on clinically important outcomes analysed in this review is needed.
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Affiliation(s)
- Milica Bjelakovic
- Clinic of Gastroenterology and Hepatology, Clinical Centre Nis, Nis, Serbia
| | - Dimitrinka Nikolova
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Goran Bjelakovic
- Clinic of Gastroenterology and Hepatology, Clinical Centre Nis, Nis, Serbia
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Christian Gluud
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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22
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Triantos C, Aggeletopoulou I, Thomopoulos K, Mouzaki A. Vitamin D-Liver Disease Association: Biological Basis and Mechanisms of Action. Hepatology 2021; 74:1065-1073. [PMID: 33405236 DOI: 10.1002/hep.31699] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 11/30/2020] [Accepted: 12/19/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Christos Triantos
- Division of GastroenterologyDepartment of Internal MedicineUniversity Hospital of PatrasPatrasGreece
| | - Ioanna Aggeletopoulou
- Division of GastroenterologyDepartment of Internal MedicineUniversity Hospital of PatrasPatrasGreece.,Division of HematologyDepartment of Internal MedicineMedical SchoolUniversity of PatrasPatrasGreece
| | - Konstantinos Thomopoulos
- Division of GastroenterologyDepartment of Internal MedicineUniversity Hospital of PatrasPatrasGreece
| | - Athanasia Mouzaki
- Division of HematologyDepartment of Internal MedicineMedical SchoolUniversity of PatrasPatrasGreece
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23
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Abstract
Until the development of direct-acting antivirals (DAAs), interferon (IFN)-based therapy had been the primary treatment strategy for patients with chronic hepatitis C, even though this therapy has a therapeutic limitations and considerable side effects. Therefore, many efforts have been made to improve the efficacy of treatment. Several clinical studies have clearly shown that supplementation with vitamin D of IFN-based therapy improves treatment efficacy. To clarify the molecular mechanisms of the effect of vitamin D on IFN-based therapy, several researchers have performed basic research with cell culture models of hepatitis C virus (HCV). Consequently, two vitamin D3 metabolites, 25-hydroxyvitamin D3 (25-(OH)D3) and 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3), have been suggested to have anti-HCV effects. 25-(OH)D3 inhibits HCV production by suppressing infectious virus assembly through reducing apolipoprotein expression, while 1α,25-(OH)2D3 inhibits HCV production by modulating IFN signaling and/or inducing various host factors associated with the inhibition of viral genome replication. In addition, an antimicrobial peptide, LL-37, which is known to be partly regulated by vitamin D, was also reported to exhibit an anti-HCV effect by disrupting infectious viral particles directly. In conclusion, vitamin D3 supplementation improves the response rate of IFN-based therapy via the direct and/or indirect anti-HCV effects of vitamin D3 metabolites.
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Affiliation(s)
- Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
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Yuan F, Wang N, Chen Y, Huang X, Yang Z, Xu Y, You K, Zhang J, Wang G, Zhuang Y, Pan T, Xiong Y, Yu X, Yang F, Li Y. Calcitriol promotes the maturation of hepatocyte-like cells derived from human pluripotent stem cells. J Steroid Biochem Mol Biol 2021; 211:105881. [PMID: 33766737 DOI: 10.1016/j.jsbmb.2021.105881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 03/07/2021] [Accepted: 03/18/2021] [Indexed: 11/23/2022]
Abstract
Human hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) represent a promising cell source for the assessment of hepatotoxicity and pharmaceutical safety testing. However, the hepatic functionality of HLCs remains significantly inferior to primary human hepatocytes. The bioactive vitamin D (VD), calcitriol, promotes the differentiation of many types of cells, and its deficiency is correlated to the severity of liver diseases. Whether calcitriol contributes to the differentiation of HLCs needs to be explored. Here, we found that the supplementation of calcitriol improved the functionalities of hPSCs-derived HLCs in P450 activities, urea production, and albumin secretion. Moreover, calcitriol also enhanced mitochondrial respiratory function with increased protein expression levels of the subunit of respiratory enzyme complexes in HLCs. Further analyses showed that the mitochondrial biogenesis regulators and mitophagy were increased by calcitriol, thus improving the mitochondrial quality. These improvements in functionality and mitochondrial condition were dependent on vitamin D receptor (VDR) because the improvements were abolished under VDR-deficient conditions. Our finding provides a cost-effective chemical process for HLC maturation to meet the demand for basic research and potential clinic applications.
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Affiliation(s)
- Fang Yuan
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; School of Life Sciences, University of Science and Technology of China, 230027, Hefei, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Ning Wang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yan Chen
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Zhen Yang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yingying Xu
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Kai You
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Jiaye Zhang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Guodong Wang
- The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China
| | - Yuanqi Zhuang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Tingcai Pan
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yue Xiong
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Xiaorui Yu
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; School of Life Sciences, University of Science and Technology of China, 230027, Hefei, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Fan Yang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese, Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
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Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells. REPORTS 2021. [DOI: 10.3390/reports4020017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.
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26
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Vitamin D deficiency in patients with chronic hepatitis D viral infection. Clin Exp Hepatol 2021; 7:141-148. [PMID: 34295980 PMCID: PMC8284160 DOI: 10.5114/ceh.2021.106505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 01/22/2021] [Indexed: 01/10/2023] Open
Abstract
Aim of the study Vitamin D deficiency is known to be associated with disease severity, unresponsiveness to treatment, and morbidity among patients with chronic viral hepatitis B and C, autoimmune hepatitis, and alcoholic hepatitis. This study aims to research vitamin D levels in patients suffering from cirrhotic and non-cirrhotic phases of hepatitis D. Material and methods 170 individuals in total were included in the study in the form of two groups: the first group of 100 patients with chronic hepatitis D (CHD), 30 of whom had cirrhosis, and the second control group of 70 individuals with similar characteristics to those of the first group in terms of age, type, and seasonal sampling. Levels of 25-hydroxy vitamin D [25(OH)D] were measured in the serum collected from patients and the control group. Results The lowest 25(OH)D levels were identified in patients with cirrhotic CHD. When these levels were compared with those of the control group, they were found to be significant (15.30 ±6.92 and 18.90 ±8.30 ng/ml, respectively, p = 0.04). 25(OH)D deficiency (< 10 ng/ml) was detected at significantly higher rates in patients with both cirrhotic and non-cirrhotic CHD compared to the healthy controls (30%, 25%, and 8.5%, respectively, p = 0.01). A significant correlation was established between 25(OH)D levels and bilirubin in patients with CHD (r = 0.252, p = 0.012). Multivariate analysis showed that chronic hepatitis D (odds ratio [OR] = 3.608, 95% confidence interval [CI]: 1.31-9.89, p = 0.013) and age (OR = 1.04, 95% CI: 1.00-1.08, p = 0.033) were associated with vitamin D deficiency. Conclusions Frequency of 25(OH)D vitamin deficiency is higher in patients with CHD. The identification of vitamin D levels and the replacement of any deficiency may create a positive effect on disease progression, morbidity, and mortality levels.
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27
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Cañamares-Orbis P, Bernal-Monterde V, Sierra-Gabarda O, Casas-Deza D, Garcia-Rayado G, Cortes L, Lué A. Impact of Liver and Pancreas Diseases on Nutritional Status. Nutrients 2021; 13:1650. [PMID: 34068295 PMCID: PMC8153270 DOI: 10.3390/nu13051650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/02/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
Liver and pancreatic diseases have significant consequences on nutritional status, with direct effects on clinical outcomes, survival, and quality of life. Maintaining and preserving an adequate nutritional status is crucial and should be one of the goals of patients with liver or pancreatic disease. Thus, the nutritional status of such patients should be systematically assessed at follow-up. Recently, great progress has been made in this direction, and the relevant pathophysiological mechanisms have been better established. While the spectrum of these diseases is wide, and the mechanisms of the onset of malnutrition are numerous and interrelated, clinical and nutritional manifestations are common. The main consequences include an impaired dietary intake, altered macro and micronutrient metabolism, energy metabolism disturbances, an increase in energy expenditure, nutrient malabsorption, sarcopenia, and osteopathy. In this review, we summarize the factors contributing to malnutrition, and the effects on nutritional status and clinical outcomes of liver and pancreatic diseases. We explain the current knowledge on how to assess malnutrition and the efficacy of nutritional interventions in these settings.
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Affiliation(s)
- Pablo Cañamares-Orbis
- Unidad de Gastroenterología, Hepatología y Nutrición, Hospital Universitario San Jorge, 22004 Huesca, Spain;
| | - Vanesa Bernal-Monterde
- Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain; (V.B.-M.); (O.S.-G.); (D.C.-D.)
- Instituto de Investigación Sanitaria (IIS) Aragón, 50009 Zaragoza, Spain; (G.G.-R.); (L.C.)
| | - Olivia Sierra-Gabarda
- Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain; (V.B.-M.); (O.S.-G.); (D.C.-D.)
- Instituto de Investigación Sanitaria (IIS) Aragón, 50009 Zaragoza, Spain; (G.G.-R.); (L.C.)
| | - Diego Casas-Deza
- Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain; (V.B.-M.); (O.S.-G.); (D.C.-D.)
- Instituto de Investigación Sanitaria (IIS) Aragón, 50009 Zaragoza, Spain; (G.G.-R.); (L.C.)
| | - Guillermo Garcia-Rayado
- Instituto de Investigación Sanitaria (IIS) Aragón, 50009 Zaragoza, Spain; (G.G.-R.); (L.C.)
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
| | - Luis Cortes
- Instituto de Investigación Sanitaria (IIS) Aragón, 50009 Zaragoza, Spain; (G.G.-R.); (L.C.)
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
| | - Alberto Lué
- Unidad de Gastroenterología, Hepatología y Nutrición, Hospital Universitario San Jorge, 22004 Huesca, Spain;
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Gonzalez-Sanchez E, El Mourabit H, Jager M, Clavel M, Moog S, Vaquero J, Ledent T, Cadoret A, Gautheron J, Fouassier L, Wendum D, Chignard N, Housset C. Cholangiopathy aggravation is caused by VDR ablation and alleviated by VDR-independent vitamin D signaling in ABCB4 knockout mice. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166067. [PMID: 33418034 DOI: 10.1016/j.bbadis.2020.166067] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/19/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Cholangiopathies are chronic liver diseases in which damaged cholangiocytes trigger a proinflammatory and profibrotic reaction. The nuclear vitamin D receptor (VDR) is highly expressed in cholangiocytes and exerts immune-regulatory functions in these cells. In the present study, we examined the protective function of VDR and other vitamin D signaling pathways in chronic cholangiopathy and cholangiocytes. METHODS Vdr was invalidated in Abcb4 knockout mice, a widely used animal model of chronic cholangiopathy. The impact of vitamin D signaling on cholangiopathy features was examined in vivo and in cholangiocytes (primary and cell lines). RESULTS Cholangiopathy features (i.e, cholestasis, ductular reaction and fibrosis) were aggravated in Vdr;Abcb4 double knockout mice compared to the Abcb4 simple knockout, and associated with an overexpression of proinflammatory factors. The proinflammatory phenotype of cholangiocytes was also exacerbated following VDR silencing in vitro. The expression of proinflammatory factors and the severity of cholangiopathy were reduced in the double knockout mice treated with the vitamin D analog calcipotriol or with vitamin D. In vitro, the inflammatory response to TNFα was significantly reduced by calcipotriol in biliary cells silenced for VDR, and this effect was abolished by co-silencing the plasma membrane receptor of vitamin D, protein disulfide-isomerase A3 (PDIA3). CONCLUSIONS Our results demonstrate an anti-inflammatory role of VDR signaling in cholangiocytes and cholangiopathy. They also provide evidence for PDIA3-mediated anti-inflammatory effects of vitamin D and vitamin D analog in these settings.
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Affiliation(s)
- Ester Gonzalez-Sanchez
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Inovarion, Paris, France; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
| | - Haquima El Mourabit
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Marion Jager
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Marie Clavel
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Inovarion, Paris, France
| | - Sophie Moog
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Inovarion, Paris, France.
| | - Javier Vaquero
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; LPP (Laboratoire de Physique des Plasmas, UMR 7648), Sorbonne Université, Centre National de la Recherche Scientifique (CNRS), Ecole Polytechnique, 75005 Paris, France.
| | - Tatiana Ledent
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Axelle Cadoret
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Jérémie Gautheron
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Dominique Wendum
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP) Sorbonne Université, Hôpital St Antoine, Paris, France.
| | | | - Chantal Housset
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; AP-HP, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR, MIVB-H), Department of Hepatology, Saint-Antoine Hospital, Paris, France.
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Cheng WZ, Lin YL, Su YC, Lin MC, Tseng CH, Lin RM, Huang ST. Post-surgery cholecystectomy, hepatectomy, and pancreatectomy patients increase the risk of osteoporotic vertebral fracture. J Bone Miner Metab 2021; 39:174-185. [PMID: 32757040 DOI: 10.1007/s00774-020-01129-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/11/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Data is currently lacking regarding association between the cholecystectomy/hepatectomy/pancreatectomy and the development of osteoporotic fracture. A retrospective cohort study was conducted to investigate the relationship between cholecystectomy/hepatectomy/pancreatectomy and the subsequent risk of developing osteoporotic fracture. MATERIALS AND METHODS Patients having undergone cholecystectomy, hepatectomy, or pancreatectomy between 2000 and 2012 were selected from the All Population Based Hospitalization File as the surgery cohort (n = 304,081), which was frequency matched with the control cohort (n = 304,081). The Cox proportional hazard model and Kaplan-Meier analysis were applied to measure the hazard ratios and the cumulative incidence of osteoporotic fracture. RESULTS A total of 1136 patients in the surgery cohort and 1179 patients in the control cohort were newly diagnosed with osteoporotic fracture. The overall osteoporotic fracture risk in the surgery cohort was 1.12-fold higher [95% confidence interval (CI), 1.03-1.21]. Specifically, surgery cohort had higher vertebral fracture risk than non-surgery cohort [adjusted hazard ratio (aHR) 1.12, Cl, 1.03-1.22]. In addition, patients underwent cholecystectomy (includes open and laparoscopic approaches), hepatectomy (only open approach), and pancreatectomy group (only open approach) were 1.10 (95% CI, 1.01-1.19), 1.49 (95% CI, 1.10-2.01), and 1.88 (95% CI, 1.23-2.87) times more likely to develop osteoporotic fracture, respectively. No significant difference of osteoporotic fracture risk was observed between open and laparoscopic cholecystectomy. The risk of osteoporotic fracture was significantly increased in females, patients aged ≥ 40 years old, and patients with some comorbidity. CONCLUSIONS Patients post cholecystectomy, hepatectomy, or pancreatectomy significantly increased risk of developing osteoporotic fracture, suggesting closer attention in post-operative care is needed.
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Affiliation(s)
- Wei-Zen Cheng
- Department of Chinese Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, 40447, Taiwan
| | - Yun-Lan Lin
- Department of Chinese Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, 40447, Taiwan
| | - Yuan-Chih Su
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Mei-Chen Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Chang-Hsing Tseng
- Tainan Municipal An-Nan Hospital-China Medical University, No. 66, Section 2, Changhe Road, Annan District, Tainan city, 70965, Taiwan
| | - Ruey-Mo Lin
- Tainan Municipal An-Nan Hospital-China Medical University, No. 66, Section 2, Changhe Road, Annan District, Tainan city, 70965, Taiwan
| | - Sheng-Teng Huang
- Department of Chinese Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, 40447, Taiwan.
- Tainan Municipal An-Nan Hospital-China Medical University, No. 66, Section 2, Changhe Road, Annan District, Tainan city, 70965, Taiwan.
- School of Chinese Medicine, China Medical University, Taichung, Taiwan.
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
- Research Center for Chinese Herbal Medicine, China Medical University, Taichung, Taiwan.
- Department of Medical Research, Cancer Research Center for Traditional Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.
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Fiorino S, Zippi M, Gallo C, Sifo D, Sabbatani S, Manfredi R, Rasciti E, Rasciti L, Giampieri E, Corazza I, Leandri P, de Biase D. The rationale for a multi-step therapeutic approach based on antivirals, drugs and nutrients with immunomodulatory activity in patients with coronavirus-SARS2-induced disease of different severities. Br J Nutr 2021; 125:275-293. [PMID: 32703328 PMCID: PMC7431858 DOI: 10.1017/s0007114520002913] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 06/28/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023]
Abstract
In December 2019, a novel human-infecting coronavirus, named Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), was recognised to cause a pneumonia epidemic outbreak with different degrees of severity in Wuhan, Hubei Province in China. Since then, this epidemic has spread worldwide; in Europe, Italy has been involved. Effective preventive and therapeutic strategies are absolutely required to block this serious public health concern. Unfortunately, few studies about SARS-CoV-2 concerning its immunopathogenesis and treatment are available. On the basis of the assumption that the SARS-CoV-2 is genetically related to SARS-CoV (about 82 % of genome homology) and that its characteristics, like the modality of transmission or the type of the immune response it may stimulate, are still poorly known, a literature search was performed to identify the reports assessing these elements in patients with SARS-CoV-induced infection. Therefore, we have analysed: (1) the structure of SARS-CoV-2 and SARS-CoV; (2) the clinical signs and symptoms and pathogenic mechanisms observed during the development of acute respiratory syndrome and the cytokine release syndrome; (3) the modification of the cell microRNome and of the immune response in patients with SARS infection; and (4) the possible role of some fat-soluble compounds (such as vitamins A, D and E) in modulating directly or indirectly the replication ability of SARS-CoV-2 and host immune response.
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Affiliation(s)
- Sirio Fiorino
- Medicine Department, Internal Medicine Unit, Budrio Hospital Azienda USL, Budrio, 40054 Bologna, Italy
- Medicine Department, Internal Medicine Unit C, Maggiore Hospital Azienda USL, 40100 Bologna, Italy
| | - Maddalena Zippi
- Gastroenterology and Hepatology Department, Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, 00100 Rome, Italy
| | - Claudio Gallo
- Medicine Department, Internal Medicine Unit, Budrio Hospital Azienda USL, Budrio, 40054 Bologna, Italy
| | - Debora Sifo
- Medicine Department, Internal Medicine Unit, Budrio Hospital Azienda USL, Budrio, 40054 Bologna, Italy
| | - Sergio Sabbatani
- Gastroenterology and Hepatology Department, Infective Disease Unit, Policlinico S. Orsola-Malpighi, University of Bologna, 40100 Bologna, Italy
| | - Roberto Manfredi
- Gastroenterology and Hepatology Department, Infective Disease Unit, Policlinico S. Orsola-Malpighi, University of Bologna, 40100 Bologna, Italy
| | - Edoardo Rasciti
- Unit of Radiodiagnostics, Ospedale degli Infermi, 48018 Faenza, AUSL Romagna, Italy
| | - Leonardo Rasciti
- Medicine Department, Internal Medicine Unit, Budrio Hospital Azienda USL, Budrio, 40054 Bologna, Italy
| | - Enrico Giampieri
- Experimental, Diagnostic and Specialty Medicine Department, University of Bologna, 40100 Bologna, Italy
| | - Ivan Corazza
- Experimental, Diagnostic and Specialty Medicine Department, University of Bologna, 40100 Bologna, Italy
| | - Paolo Leandri
- Medicine Department, Internal Medicine Unit C, Maggiore Hospital Azienda USL, 40100 Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology, University of Bologna, 40100 Bologna, Italy
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Name JJ, Vasconcelos AR, Souza ACR, Fávaro WJ. Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID‑19 (Review). Int J Mol Med 2021; 47:11. [PMID: 33448317 PMCID: PMC7834962 DOI: 10.3892/ijmm.2021.4844] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in December, 2019 in Wuhan, China. Since then, it has continued to spread rapidly in numerous countries, while the search for effective therapeutic options persists. Coronaviruses, including SARS-CoV-2, are known to suppress and evade the antiviral responses of the host organism mediated by interferon (IFN), a family of cytokines that plays an important role in antiviral defenses associated with innate immunity, and has been used therapeutically for chronic viral diseases and cancer. On the other hand, OncoTherad, a safe and effective immunotherapeutic agent in the treatment of non-muscle invasive bladder cancer (NMIBC), increases IFN signaling and has been shown to be a promising therapeutic approach for COVID-19 in a case report that described the rapid recovery of a 78-year-old patient with NMIBC with comorbidities. The present review discusses the possible synergistic action of OncoTherad with vitamin D, zinc and glutamine, nutrients that have been shown to facilitate immune responses mediated by IFN signaling, as well as the potential of this combination as a therapeutic option for COVID-19.
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Affiliation(s)
- José João Name
- Kilyos Assessoria, Cursos e Palestras (Kilyos Nutrition), São Paulo, SP 01311‑100, Brazil
| | - Andrea Rodrigues Vasconcelos
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP 05508‑000, Brazil
| | | | - Wagner José Fávaro
- Laboratory of Urogenital Carcinogenesis and Immunotherapy, University of Campinas, Campinas, SP 13083‑970, Brazil
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Chen HW, Chiu YL, Hsieh TY, Chen PJ, Huang TY, Lin HH, Shih YL, Lin JC. Relationships Between Vitamin D Status and Cytokine: Results from Interferon-Based Therapy in Non-Cirrhotic, Treatment-Naïve Patients with Chronic Hepatitis C Infection. J Inflamm Res 2021; 13:1207-1218. [PMID: 33402842 PMCID: PMC7778440 DOI: 10.2147/jir.s283768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022] Open
Abstract
Background Vitamin D contributes to bone health and extra-skeletal effects. The mechanisms underlying vitamin D metabolism have not been extensively evaluated. The relationships between vitamin D and inflammatory cytokines are debated. Our objective was to investigate whether supplemental interferons are associated with longitudinal change of vitamin D status in humans. Methods A total of 48 patients with 24 or 48 weeks of pegylated interferon-α plus ribavirin therapy were examined for serum 25-hydroxyvitamin D (25[OH]D) level before treatment, at the end of treatment, and 24 weeks after treatment. In addition, we analyzed publicly available RNA sequencing data from accession GSE42697 and GSE7123 in the Gene Expression Omnibus. Findings The overall sustained virologic response (SVR) rate was 62.5%. There was no statistically significant association between baseline 25(OH)D concentrations and liver fibrosis. In patients with SVR, serum 25(OH)D increased markedly at end-of-treatment and decreased markedly by the end of the 24-week follow-up period. In the non-SVR group, this treatment-dependent change was lost. In gene expression analysis, the vitamin D biosynthesis process was activated in subjects with SVR, but not in patients without SVR. Furthermore, vitamin D receptor (VDR) signaling in peripheral blood mononuclear cells (PBMCs) was triggered in marked responders but not in poor responders. Conclusion In the aggregate, these data suggest that interferons have a regulatory influence on vitamin D status that can contribute to VDR signaling in PBMCs.
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Affiliation(s)
- Hsuan-Wei Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Lin Chiu
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Peng-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tien-Yu Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsuan-Hwai Lin
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jung-Chun Lin
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Wu P, Zhang R, Luo M, Zhang T, Pan L, Xu S, Pan L, Ren F, Ji C, Hu R, Noureddin M, Pandol SJ, Han YP. Liver Injury Impaired 25-Hydroxylation of Vitamin D Suppresses Intestinal Paneth Cell defensins, leading to Gut Dysbiosis and Liver Fibrogenesis. Am J Physiol Gastrointest Liver Physiol 2020; 319:G685-G695. [PMID: 33084400 PMCID: PMC7792671 DOI: 10.1152/ajpgi.00021.2020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 08/26/2020] [Accepted: 09/30/2020] [Indexed: 01/31/2023]
Abstract
Vitamin D deficiency is co-prevalent with various liver diseases including cirrhosis, while the underlying mechanism remains elusive. Vitamin D receptor (VDR) is abundantly expressed in the distal region of small intestine, where the Paneth cells are enriched, suggesting that vitamin D signaling may modulates the intestinal Paneth cells and their production of defensins to restrain microbiome growth in the small intestine. In this study we found that in carbon tetrachloride-induced liver injury, hepatic 25-hydroxylation of vitamin D was impaired, leading to down regulated expression of Paneth cell fensins in the small intestine, gut dysbiosis, and endotoxinemia. While intraperitoneal injection of endotoxin (lipopolysaccharides) alone did not elicit liver fibrosis, it exacerbated the carbon tetrachloride initiated liver fibrogenesis. Oral gavage of synthetic Paneth cell alpha-defensin 5 (DEFA5) restored the homeostasis of gut microbiota, reduced endotoxemia, relieved liver inflammation, and ameliorated liver fibrosis. Likewise, Cholestyramine, cationic resin that can sequestrate endotoxin in the intestine, attenuated the liver fibrosis as well. Fecal transplant of the microbes derived from the DEFA5-treated donors improved liver fibrosis in the recipient mice. The intestinal Vdrconditional knockout mice exhibited reduction of Paneth cell defensins and lysozyme production, and worsened liver injury and fibrogenesis. Thus, liver injury impairs synthesis of 25(OH)VD3, which consequently impedes the Paneth cells functions in the small intestine, leading to gut dysbiosis for liver fibrogenesis.
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Affiliation(s)
- Pengfei Wu
- College of Life Sciences, Sichuan University, China
| | - Ruofei Zhang
- College of Life Sciences, Sichuan University, China
| | - Mei Luo
- Medicine, Public Health and Clinical Center of Chengdu, China
| | - Tianci Zhang
- College of Life Sciences, Sichuan University, China
| | - Lisha Pan
- College of Life Sciences, Sichuan University, China
| | - Siya Xu
- College of Life Sciences, Sichuan University, China
| | - Liwei Pan
- The College of Life Sciences, Sichuan University, China
| | | | - Cheng Ji
- Medicine, Keck School of Medicine USC, United States
| | - Richard Hu
- Medicine, David Geffen School of Medicine, United States
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Sriphoosanaphan S, Thanapirom K, Suksawatamnuay S, Thaimai P, Sittisomwong S, Sonsiri K, Srisoonthorn N, Teeratorn N, Tanpowpong N, Chaopathomkul B, Treeprasertsuk S, Poovorawan Y, Komolmit P. Changes in hepatic fibrosis and vitamin D levels after viral hepatitis C eradication using direct-acting antiviral therapy. BMC Gastroenterol 2020; 20:346. [PMID: 33069226 PMCID: PMC7568415 DOI: 10.1186/s12876-020-01485-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022] Open
Abstract
Background Vitamin D (VD) is important in hepatic fibrogenesis in animal models and human studies. VD deficiency is associated with liver fibrosis progression. Metabolic dysfunction of the liver, as an intermediate organ for VD metabolism, contributes partly to this deficiency. We hypothesized that improving hepatic fibrosis and inflammation in chronic hepatitis C (CHC) patients after eradication with direct-acting antivirals (DAA) would increase 25-hydroxyVD [25(OH)VD] levels. Methods Eighty CHC patients (17 chronic hepatitis, and 63 cirrhosis) were enrolled. Baseline characteristics, hepatitis C viral load (VL), genotypes, liver enzymes and liver stiffness measurements (LSM) were assessed at baseline. Blood samples for 25(OH)VD and the procollagen type III N-terminal peptide (P3NP) were collected at baseline, 24 and 48 weeks. LSMs were re-evaluated at 48 weeks. Serum 25(OH)VD levels < 30 ng/mL were defined as VD insufficiency/deficiency. Paired t-tests were used for statistical analyses.
Results Among 80 patients, the mean age was 57.7 ± 10.5 years, and 52.5% were men. The mean VL was 6.1 ± 0.7 logIU/mL with genotype 1 predominance (55%). All patients achieved sustained virological response. The alanine aminotransferase levels decreased from 79.9 ± 53.3 U/L at baseline to 25.7 ± 17.2 and 22.3 ± 11.0 U/L at 24 and 48 weeks, respectively (p < 0.001). The mean LSM decreased from 19.2 ± 15.3 to 11.7 ± 8.0 kPa at 48 weeks (p < 0.001). The P3NP levels decreased from 43.6 ± 22.0 ng/mL before treatment to 35.7 ± 21.1 and 29.4 ± 15.0 ng/mL at 24 and 48 weeks, respectively (p < 0.001). The proportions of VD insufficiency/deficiency were 72.5%, 91.3%, and 86.5% at baseline, 24 and 48 weeks, respectively. The 25(OH)VD levels decreased from 26.3 ± 10.7 ng/mL at baseline to 20.8 ± 8.1 and 20.8 ± 8.5 ng/mL at 24 and 48 weeks, respectively (p < 0.001). Conclusions Curative treatment with DAA attenuated the liver stiffness and inflammation but did not improve VD levels. Over 80% of patients remained VD insufficient/deficient. Whether VD replacement during and after DAA therapy can improve hepatic fibrosis remains unclear.
Trial registration The Thai Clinical Trial Registry as TCTR20161025001 (31 October 2016). http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=2136.
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Affiliation(s)
- Supachaya Sriphoosanaphan
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand
| | - Kessarin Thanapirom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand.,Liver Fibrosis and Cirrhosis Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Sirinporn Suksawatamnuay
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand.,Liver Fibrosis and Cirrhosis Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Panarat Thaimai
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Sukanya Sittisomwong
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kanokwan Sonsiri
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Nunthiya Srisoonthorn
- Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand
| | - Nicha Teeratorn
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Nattaporn Tanpowpong
- Department of Radiology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Bundit Chaopathomkul
- Department of Radiology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Piyawat Komolmit
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand. .,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand. .,Liver Fibrosis and Cirrhosis Research Unit, Chulalongkorn University, Bangkok, Thailand.
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Siddiqui M, Manansala JS, Abdulrahman HA, Nasrallah GK, Smatti MK, Younes N, Althani AA, Yassine HM. Immune Modulatory Effects of Vitamin D on Viral Infections. Nutrients 2020; 12:E2879. [PMID: 32967126 PMCID: PMC7551809 DOI: 10.3390/nu12092879] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/29/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023] Open
Abstract
Viral infections have been a cause of mortality for several centuries and continue to endanger the lives of many, specifically of the younger population. Vitamin D has long been recognized as a crucial element to the skeletal system in the human body. Recent evidence has indicated that vitamin D also plays an essential role in the immune response against viral infections and suggested that vitamin D deficiency increases susceptibility to viral infections as well as the risk of recurrent infections. For instance, low serum vitamin D levels were linked to increased occurrence of high burdens viral diseases such as hepatitis, influenza, Covid-19, and AIDS. As immune cells in infected patients are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D-deficient individuals with an infectious disease may extend beyond the impact on bone and calcium homeostasis. Even though numerous studies have highlighted the effect of vitamin D on the immune cells, vitamin D's antiviral mechanism has not been fully established. This paper reviews the recent mechanisms by which vitamin D regulates the immune system, both innate and adaptive systems, and reflects on the link between serum vitamin D levels and viral infections.
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Affiliation(s)
- Maheen Siddiqui
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
| | - Judhell S. Manansala
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
| | - Hana A. Abdulrahman
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Gheyath K. Nasrallah
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Maria K. Smatti
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Nadin Younes
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Asmaa A. Althani
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Hadi M. Yassine
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
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Sari E, Oztay F, Tasci AE. Vitamin D modulates E-cadherin turnover by regulating TGF-β and Wnt signalings during EMT-mediated myofibroblast differentiation in A459 cells. J Steroid Biochem Mol Biol 2020; 202:105723. [PMID: 32603782 DOI: 10.1016/j.jsbmb.2020.105723] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/07/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022]
Abstract
Vitamin D (VitD) has an anti-fibrotic effect on fibrotic lungs. It reduces epithelial-mesenchymal transition (EMT) on tumors. We aimed to investigate target proteins of VitD for the regression of EMT-mediated myofibroblast differentiation. A group of A549 cells were treated with 5 % cigarette smoke extract (CSE) and 5 %CSE + TGF-β (5 ng/ml) to induce EMT. The others were treated with 50 nM VitD 30 min before %5CSE and TGF-β treatments. All cells were collected at 24, 48 and 72 h following 5 %CSE and TGF-β administrations. The expression of p120ctn and NEDD9 proteins acted on E-cadherin turnover in addition to activations of TGF-β and Wnt pathways were examined in these cells and fibrotic human lungs. CSE and TGF-β induced EMT by reducing E-cadherin, p-VDR, SMAD7 and DKK1, increasing α-SMA, p120ctn, Kaiso, NEDD9 and stimulating TGF-β and Wnt/β-catenin signalings in A549 cells. VitD administration reversed these alterations and regressed EMT. Co-immunoprecipitation analysis revealed p-VDR interaction with β-catenin and Kaiso in fibrotic and non-fibrotic human lungs. VitD pre-treatments reduced TGF-β and Wnt/β-catenin signalings by increasing p-VDR, protected from E-cadherin degradation and led to the regression of EMT in A549 cells treated with CSE and TGF-β. Finally, VitD supplementation combined with anti-fibrotic therapeutics can be suggested for treatment of pulmonary fibrosis, which may be developed by smoking, in cases of VitD deficiency.
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Affiliation(s)
- Ezgi Sari
- Istanbul University, Faculty of Science, Department of Biology, 34134, Vezneciler, Istanbul, Turkey.
| | - Fusun Oztay
- Istanbul University, Faculty of Science, Department of Biology, 34134, Vezneciler, Istanbul, Turkey.
| | - Ahmet Erdal Tasci
- Lung Transplantation Center, Department of Thoracic Surgery, Kartal Kosuyolu High Speciality Educational and Research Hospital, Kartal, Istanbul, Turkey.
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Jeong JY, Jun DW, Park SJ, Sohn JH, Kim SG, Lee SW, Jeong SW, Kim MY, Kim W, Shim JJ, Kim HS, Suk KT, Ahn SB. Effects of vitamin D supplements in patients with chronic hepatitis C: a randomized, multi-center, open label study. Korean J Intern Med 2020; 35:1074-1083. [PMID: 31710801 PMCID: PMC7487303 DOI: 10.3904/kjim.2018.273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 11/05/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS We aimed to assess the role of vitamin D supplementation in the response to pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV) treatment in patients with chronic hepatitis C (CHC). METHODS Our study was a multi-center, randomized controlled trial in 11 hospitals. CHC patients were randomly assigned (1:1) to two groups namely, PEGIFN-α plus RBV (control group) or PEG-IFN-α plus RBV + vitamin D (800 IU daily) (vitamin D group). The primary end-point was the rate of sustained virologic response (SVR). RESULTS One hundred forty eight CHC patients were randomly assigned to two groups. Seventy-one patients received the PEG-IFN-α plus RBV and 77 patients received the PEG-IFN-α plus RBV + vitamin D. A total of 105 patients completed the study (control group, 47 vs. vitamin D group, 58). Baseline characteristics were mostly similar in both the groups. There was a modest but non-significant increase in SVR in the vitamin D group compared to the control group with the intention to treat analysis (64.0% vs. 49.3 %, p = 0.071) as well as in the per protocol analysis (control group vs. vitamin D group: 74.5% vs. 84.5%, p = 0.202). Fifty-two patients (73.2%) in the control group and 63 patients (81.8%) in the vitamin D group experienced at least one adverse event. The drop-out rate due to adverse effects was not different between both groups (control group vs. vitamin D group: 19.7% vs. 10.4%, p = 0.111). CONCLUSION Vitamin D supplement did not increase SVR in treatment naïve patients with CHC irrespective of genotype.
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Affiliation(s)
- Jae Yoon Jeong
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Seoul, Korea
- Correspondence to Dae Won Jun, M.D. Department of Internal Medicine, Hanyang University College of Medicine, 222-1 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea. Tel: +82-2-2290-8338, Fax: +82-2-972-0068, E-mail:
| | - Sol Ji Park
- Department of Clinical Pharmacology, Sungkyunkwan University, Seoul, Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Se Whan Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju Severance Christian Hospital, Wonju, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Eulji University School of Medicine, Seoul, Korea
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Relationship Between 25-HydroxyVitamin D Level and Liver Stiffness in Patients with Chronic Hepatitis B Using Transient Elastography. HEPATITIS MONTHLY 2020. [DOI: 10.5812/hepatmon.100891] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Studies are limited on the relationship between vitamin D levels and liver fibrosis in patients with hepatitis B. Objectives: A study was conducted to investigate the relationship between 25-hydroxyvitamin D levels and liver stiffness in patients with hepatitis B. Methods: In a cross-sectional study, serum 25-hydroxyvitamin D levels and liver stiffness, measured by transient elastography (TE), were evaluated in 281 patients with hepatitis B. The predictors of liver stiffness and its relationship with 25-hydroxyvitamin D level, coinfection with hepatitis D, age, and viral load were determined using multivariate analysis. Results: A significant correlation was observed between 25-hydroxyvitamin D deficiency and liver stiffness. Based on multivariate analysis, factors that were independently associated with advanced liver fibrosis included vitamin D level (P < 0.001), coinfection with hepatitis D (P < 0.001), and age (P < 0.001). Among 281 patients, the frequency of vitamin D deficiency (< 10 ng/mL), insufficiency (≥ 10 and < 20 ng/mL), and adequacy (≥ 30 ng/mL) was 40 (14.2%), 150 (53.4%), and 91 (32.4%), respectively. Conclusions: In hepatitis B patients, vitamin D deficiency was independently associated with advanced liver fibrosis. An increase in age and coinfection with hepatitis D were also directly related to liver stiffness.
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Zhang Y, Jiang X, Li X, Găman MA, Kord-Varkaneh H, Rahmani J, Salehi-Sahlabadi A, Day AS, Xu Y. Serum Vitamin D Levels and Risk of Liver Cancer: A Systematic Review and Dose-Response Meta-Analysis of Cohort Studies. Nutr Cancer 2020; 73:1-9. [PMID: 32705896 DOI: 10.1080/01635581.2020.1797127] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Data regarding the relationship between serum vitamin D levels and the risk of liver cancer are conflicting. Therefore, we performed a systematic review and dose-response meta-analysis of all available data of cohort studies on the association of 25-OH-vitamin-D levels with the risk of hepatocellular carcinoma. We conducted a systematic search in PubMed-MEDLINE, Scopus, Cochrane and Web of Science databases for prospective observational studies conducted on the general population from inception to May 2019. Six studies provided data from 6357 participants. According to the pooled HR, the subjects with the highest serum concentrations of vitamin D had a 47% lower risk of liver cancer vs. the subjects with the lowest serum concentrations of vitamin D (pooled HR: 0.53, 95% CI: 0.41-0.68; P < 0.001). There was no significant heterogeneity among the studies (P = 0.431, I2 = 0.0). The pooled HR from the random-effects dose-response model indicated an indirect significant linear association between vitamin D and the risk of liver cancer (coef = -0.017, P < 0.001). However, there was no significant nonlinear dose-response association between serum vitamin D and the risk of liver cancer (coef = -0.0001, P = 0.342). The evidence from this meta-analysis suggests that there may be an inverse relationship between serum vitamin D levels and the risk of liver cancer.
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Affiliation(s)
- Yonggui Zhang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xuefeng Jiang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xiangjun Li
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, China
| | - Mihnea-Alexandru Găman
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Hamed Kord-Varkaneh
- Department of Clinical Nutrition and Dietetics, Student Research Committee, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Rahmani
- Department of Clinical Nutrition and Dietetics, Student Research Committee, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ammar Salehi-Sahlabadi
- Department of Clinical Nutrition and Dietetics, Student Research Committee, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Andrew S Day
- Department of Paediatrics, University of Otago, Christchurch, New Zealand
| | - Yan Xu
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
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Abstract
OBJECTIVE(S) Increasing evidence indicates that vitamin D status is linked to severity of liver cirrhosis and patients' survival. However, the potential role of vitamin D-related immunomodulation in hepatic decompensation and patients' mortality in relation to vitamin D deficiency remains unknown. The aim of the current study is to evaluate the association between vitamin D status and vitamin D binding protein (VDBP) levels with serum cytokine and lipopolysaccharide binding protein (LBP) and to examine their role on disease severity and cirrhotics' mortality. METHODS One hundred consecutive Caucasian patients with liver cirrhosis were enrolled in the study. 25(OH)D, VDBP, and LBP concentrations were assessed by ELISA. Cytokine tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), IL-1β, IL-8, IL-10, and IL-12 levels were determined by Cytometric Bead Array. RESULTS 25(OH)D levels were inversely correlated with CP score, MELD, IL-6, and CP stage and VDBP levels with CP score, MELD, IL-6, IL-8, LBP, and CP stage. Cirrhotics with 25(OH)D deficiency and severe deficiency had significantly higher CP score, increased IL-6 levels and lower VDBP levels. In the multivariate analysis, the independent prognostic factors associated with patients' survival were CP stage B [hazard ratio = 6.75; 95% confidence interval (CI) 1.32, 34.43; P = 0.022], CP stage C (hazard ratio = 7.39; 95% CI 1.41, 38.81; P = 0.018), the presence of hepatocellular carcinoma (hazard ratio = 4.50; 95% CI 1.54, 13.13; P = 0.006) and 25(OH)D levels (hazard ratio = 0.87; 95% CI 0.80, 0.95; P = 0.002). CONCLUSION The results show that vitamin D status and VDBP levels are associated with liver cirrhosis severity and patients' mortality, possibly through a proinflammatory immune response.
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Low serum 25-hydroxyvitamin D levels are associated with liver injury markers in the US adult population. Public Health Nutr 2020; 23:2915-2922. [PMID: 32576302 DOI: 10.1017/s1368980020000348] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To examine the associations between serum 25-hydroxyvitamin D (25(OH)D) levels and serum liver enzymes in a representative sample of US adults. DESIGN The cross-sectional study sample consisted of 24 229 adults with data on serum 25(OH)D levels and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transaminase (GGT) concentrations, in addition to data on other potential confounders. Multivariate logistic regression and linear regression were applied to assess the associations between serum 25(OH)D levels and ALT, AST, ALP and GGT concentrations. SETTING The National Health and Nutrition Examination Survey, 2001-2006. PARTICIPANTS The cross-sectional study sample consisted of 24 229 adults. RESULTS We found a significant association between low serum 25(OH)D levels (<30 nmol/l) and ALP levels in all participants (OR 2·67; 95 % CI 1·98, 3·59; P < 0·001), a confirmed healthy population (OR 3·02; 95 % CI 2·25, 4·07; P < 0·001) and individuals with viral hepatitis (OR 2·87; 95 % CI 1·52, 5·44; P = 0·006) compared with those who had normal 25(OH)D levels (>50 nmol/l). Moreover, in both the logistic regression and linear regression, the associations between 25(OH)D levels and ALP levels were stronger in the subgroups with obesity. No association was present between ALT, AST or GGT levels and serum 25(OH)D levels in this population. CONCLUSIONS The results of the present study provide epidemiological evidence that vitamin D deficiency is associated with liver ALP levels in humans. This finding suggests a potential adverse effect of low 25(OH)D levels on human liver function. However, the underlying mechanisms still need further investigation.
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Udomsinprasert W, Jittikoon J, Sukkho S, Pojarassangkul N, Sangroongruangsri S, Chaikledkaew U. Decreased circulating vitamin D reflects adverse outcomes of hepatitis C virus infection: A systematic review and meta-analysis. J Infect 2020; 81:585-599. [PMID: 32553842 DOI: 10.1016/j.jinf.2020.06.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/21/2020] [Accepted: 06/12/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES This study aimed to clarify associations of circulating vitamin D and its status with severity of HCV infection. METHODS We performed systemic literature search in PubMed, Scopus, and Cochrane library databases from inception until the end of December 2019 with terms related to vitamin D and hepatitis C. RESULTS A total of 28 studies consisting of 7736 HCV-infected patients and 14061 control subjects without liver diseases were included. Compared to controls, circulating vitamin D levels were significantly lessened in HCV-infected patients (mean difference, MD=-14.15, 95% CI: -20.51 to -7.80). Remarkably decreased circulating vitamin D was found in the patients with severe fibrosis (MD=-3.38, 95% CI: -4.51 to -2.25), non-achieving SVR (MD=-2.99, 95%CI: -5.55 to -0.42), and advanced inflammation (MD=-4.68, 95% CI: -8.50 to -0.86). Low vitamin D status (<20 ng/mL) was significantly associated with increased odds of HCV infection (pooled OR=2.41, 95% CI: 1.48 to 3.95). Besides, HCV-infected patients with low vitamin D status showed significantly escalated odds of severe fibrosis and non-achieving SVR (pooled OR=1.70, 95% CI: 1.27 to 2.26; pooled OR=2.04, 95% CI: 1.62 to 2.57, respectively). CONCLUSION HCV-infected patients with declined circulating vitamin D levels were associated with severe fibrosis, non-achieving SVR, and advanced inflammation.
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Affiliation(s)
- Wanvisa Udomsinprasert
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhaya Road, Rajathevi, Bangkok 10400, Thailand.
| | - Jiraphun Jittikoon
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhaya Road, Rajathevi, Bangkok 10400, Thailand.
| | - Sorraya Sukkho
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhaya Road, Rajathevi, Bangkok 10400, Thailand.
| | - Nicha Pojarassangkul
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhaya Road, Rajathevi, Bangkok 10400, Thailand.
| | - Sermsiri Sangroongruangsri
- Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
| | - Usa Chaikledkaew
- Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand; Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Bangkok 10400, Thailand.
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Kim TH, Yun SG, Choi J, Goh HG, Lee HA, Yim SY, Choi SJ, Lee YS, Yoon EL, Jung YK, Seo YS, Kim JH, Yim HJ, Yeon JE, Byun KS, Um SH. Differential Impact of Serum 25-Hydroxyvitamin D3 Levels on the Prognosis of Patients with Liver Cirrhosis According to MELD and Child-Pugh Scores. J Korean Med Sci 2020; 35:e129. [PMID: 32419396 PMCID: PMC7234861 DOI: 10.3346/jkms.2020.35.e129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 03/03/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Prognosis of patients with diverse chronic diseases is reportedly associated with 25-hydroxyvitamin D levels. In this study, we investigated the potential role of 25-hydroxyvitamin D3 (25[OH]D3) levels in improving the predictive power of conventional prognostic models for patients with liver cirrhosis. METHODS We investigated clinical findings, including serum 25(OH)D3 levels at admission, of 155 patients with cirrhosis who were followed up for a median of 16.9 months. RESULTS Median 25(OH)D3 levels were significantly different among patients exhibiting Child-Pugh grades A, B, and C. Mortality, including urgent transplantation, was significantly associated with 25(OH)D3 levels in univariate analysis. Severe vitamin-D deficiency (serum 25[OH]D3 level < 5.0 ng/mL) was significantly related to increased mortality, even after adjusting for Child-Pugh and Model for End-stage Liver Disease (MELD) scores. In particular, the presence of severe vitamin D deficiency clearly defined a subgroup with significantly poorer survival among patients with Child-Pugh scores of 5-10 or MELD scores ≤ 20. A new combination model of MELD score and severe vitamin D deficiency showed significantly more accurate predictive power for short- and long-term mortality than MELD scores alone. Additionally, serum 25(OH)D3 levels and new model scores were significantly associated with the development of spontaneous bacterial peritonitis, overt encephalopathy, and acute kidney injury. CONCLUSION Serum 25(OH)D3 level is an independent prognostic factor for patients with liver cirrhosis and has a differential impact on disease outcomes according to MELD and Child-Pugh scores.
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Affiliation(s)
- Tae Hyung Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Seung Gyu Yun
- Department of Laboratory Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jimi Choi
- Department of Biostatistics, Korea University College of Medicine, Seoul, Korea
| | - Hyun Gil Goh
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Seong Ji Choi
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Young Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Eileen L Yoon
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jong Eun Yeon
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
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The association of vitamin D with hepatitis B virus replication: Bystander rather than offender. J Formos Med Assoc 2020; 119:1634-1641. [PMID: 31932201 DOI: 10.1016/j.jfma.2019.12.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/10/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/PURPOSE Low vitamin D is frequent in hepatitis B virus (HBV)-infected patients and several studies show an inverse association of serum vitamin D level with HBV viral load. However, the causal relationship remains unclear. METHODS HBV carriers receiving regular 6-month surveillance without current antiviral treatment or cirrhosis were invited to participate into this trial. The markers of HBV replication included serum HBV DNA and quantitative HBsAg (qHBsAg) levels. Those with undetectable HBV DNA or sufficient vitamin D levels, cancer or electrolyte imbalance were excluded. The eligible subjects were randomized to receive either vitamin D supplement 2000 IU per day for 2 months (vitamin D group) or none (control group). RESULTS A total of 196 HBV carriers (93 males and 103 females; mean age 51.9 ± 10.0 years) were screened. Of them, 28 patients had undetectable serum HBV DNA levels, which is defined as spontaneous viral clearance. The vitamin D levels were not different between patients with detectable HBV DNA and those without (p = 0.18). After exclusion, 149 patients were randomized to two groups: 75 in vitamin D group and 74 in control group. After 2 months vitamin D supplement, the serum vitamin D levels were significantly higher in the vitamin D group than the control group (p < 0.001). However, the serum qHBsAg and HBV DNA levels were comparable between these two groups. CONCLUSION There is no causal relationship between vitamin D and HBV replication. The role of liver reserve on serum vitamin D levels in patients with chronic HBV infection needs further investigation.
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Chokuda E, Reynolds C, Das S. Association of Low Vitamin D with Complications of HIV and AIDS: A literature Review. Infect Disord Drug Targets 2020; 20:122-142. [PMID: 30574856 DOI: 10.2174/1871526519666181221122731] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/13/2018] [Accepted: 12/14/2018] [Indexed: 06/09/2023]
Abstract
With the advent of combination antiretroviral therapy (cART), the survival of HIV patients has improved dramatically, but the complications of the disease and treatment have become an important issue in the management of HIV patients. Vitamin-D deficiency is common in HIV patients. Low vitamin-D is associated with different comorbidities in the HIV uninfected general population. In this review, we first briefly describe vitamin D synthesis and mechanism of action and we focus on the epidemiological and clinical data dealing with the relationship between vitamin D deficiency in HIV infection with several comorbidities which has been found to be increasingly common in patients living with HIV infection. We searched the PubMed database using the keywords "HIV," "vitamin D" and other common disorders or conditions that are relatively common in HIV infection. The other conditions included in the search were osteoporosis and fracture, cardiovascular disease, diabetes and insulin resistance, active tuberculosis, hepatitis-C co-infection, and HIV disease progression. Articles presenting original data as well as systematic reviews and met analysis related to HIV population were included in our analysis. Vitamin-D deficiency seems to be associated with several adverse outcomes in HIV patients but a definite cause and effect relationship with vitamin-D is yet to be confirmed in most of the cases. However, the literature supporting the efficacy of vitamin-D supplementation is lacking.
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Affiliation(s)
- Evelyn Chokuda
- Department of HIV Medicine, Coventry & Warwickshire Partnership Trust, Coventry, United Kingdom
| | - Chris Reynolds
- Department of HIV Medicine, Coventry & Warwickshire Partnership Trust, Coventry, United Kingdom
| | - Satyajit Das
- Department of HIV Medicine, Coventry & Warwickshire Partnership Trust, Coventry, United Kingdom
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Haghgoo SM, Sharafi H, Alavian SM. Serum cytokines, adipokines and ferritin for non-invasive assessment of liver fibrosis in chronic liver disease: a systematic review. Clin Chem Lab Med 2019; 57:577-610. [PMID: 30231008 DOI: 10.1515/cclm-2018-0357] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 07/27/2018] [Indexed: 02/06/2023]
Abstract
Chronic liver disease (CLD) is a major health problem worldwide. Non-alcoholic fatty liver disease (NAFLD), chronic hepatitis C (CHC), chronic hepatitis B (CHB), and alcoholic liver disease (ALD) are the most common etiologies of CLD. Liver biopsy is the gold standard for assessment of liver fibrosis, however, it is an invasive method. This review attempts to evaluate the usefulness of serum adiponectin, serum leptin, serum ferritin, serum transforming growth factor-β1 (TGF-β1), and serum platelet derived growth factor-BB (PDGF-BB) as non-invasive markers in the diagnosis of liver fibrosis/cirrhosis. A systematic search in MEDLINE, Web of Science, Scopus, and local databases was performed to identify articles published in English or Persian as of November 2017. Studies conducted among CLD patients, with biopsy proven fibrosis/cirrhosis, and providing sufficient details of patients' clinicopathological characteristics were included. In the 95 studies included, there were a total of 15,548 CLD patients. More than 83% of studies were carried out in Asia and Europe. The relationship between liver fibrosis/cirrhosis and serum levels of ferritin, adiponectin, leptin, TGF-β1, and PDGF-BB was assessed in 42, 33, 27, nine, and three studies, respectively. Serum levels of the markers, particularly ferritin, could successfully predict liver fibrosis/cirrhosis, however, these data might not be clinically replicated and further studies are needed.
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Affiliation(s)
- Seyyed Mortaza Haghgoo
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Heidar Sharafi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Middle East Liver Diseases (MELD) Center, Tehran, Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Middle East Liver Diseases (MELD) Center, Tehran, Iran
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Hoan NX, Khuyen N, Giang DP, Binh MT, Toan NL, Anh DT, Trung NT, Bang MH, Meyer CG, Velavan TP, Song LH. Vitamin D receptor ApaI polymorphism associated with progression of liver disease in Vietnamese patients chronically infected with hepatitis B virus. BMC MEDICAL GENETICS 2019; 20:201. [PMID: 31864292 PMCID: PMC6925483 DOI: 10.1186/s12881-019-0903-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 10/03/2019] [Indexed: 02/06/2023]
Abstract
Background Vitamin D derivatives and their receptor (VDR) are potent modulators of immune responses in various diseases including malignancies as well as in metabolic and infectious disorders. The impact of vitamin D receptor polymorphisms on clinical outcomes of hepatitis B virus (HBV) infection is not well understood. This study aims to investigate the potential role of VDR polymorphisms (TaqI, FokI, ApaI, and BsmI) in Vietnamese HBV infected patients and to correlate these polymorphisms with the progression of HBV-related liver disease. Methods Four hundred forty-three HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 183), liver cirrhosis (LC, n = 89) and hepatocellular carcinoma (HCC, n = 171) and 238 healthy individuals (HC) were enrolled. VDR polymorphisms were genotyped by DNA sequencing and in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of VDR polymorphisms with manifest HBV infection as well as with progression of related liver diseases mulin different genetic models. Results The VDR ApaI CA genotype was less frequent in HCC than in CHB patients in different genetic models (codominant model, OR = 0.5, 95%CI = 0.3–0.84, P = 0.004; dominant model, OR = 0.46, 95%CI = 0.27–0.76, P = 0.0023). In the recessive model, the genotype ApaI AA was found more frequently among HCC compared to CHB patients (OR = 2.56, 95%CI = 1.01–6.48, P = 0.04). Similarly, the ApaI CA genotype was less frequent in HCC than in non-HCC group codominant model, OR = 0.6, 95%CI = 0.4–0.98, dominant model, P = 0.04 and OR = 0.6, 95%CI = 0.38–0.90, P = 0.017). The ApaI genotypes CA and AA was significantly associated with higher levels of liver enzymes, bilirubin, and HBV DNA (P < 0.05). No association between TaqI, FokI and BsmI polymorphisms and any clinical outcome as well as liver disease progression was found. Conclusions Among the four investigated VDR polymorphisms, ApaI is associated with clinical outcome and liver disease progression in Vietnamese HBV infected patients.
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Affiliation(s)
- Nghiem Xuan Hoan
- Institute of Clinical Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, 108 Military Central Hospital, Tran Hung Dao Street N1, Hai Ba Trung District, Hanoi, Vietnam. .,Faculty of Tropical and Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam. .,Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany. .,Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.
| | - Nguyen Khuyen
- Department of Infectious Diseases, Duc Giang Hospital, Hanoi, Vietnam
| | - Dao Phuong Giang
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Department of Molecular Biology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Mai Thanh Binh
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Department of Gastroenterology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Nguyen Linh Toan
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.,Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
| | - Do Tuan Anh
- Department of Infectious Diseases, 103 Military Hospital, Hanoi, Vietnam
| | - Ngo Tat Trung
- Faculty of Tropical and Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam.,Department of Molecular Biology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Mai Hong Bang
- Faculty of Tropical and Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam.,Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.,Department of Gastroenterology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Christian G Meyer
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.,Duy Tan University, Da Nang, Vietnam
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.,Duy Tan University, Da Nang, Vietnam
| | - Le Huu Song
- Institute of Clinical Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, 108 Military Central Hospital, Tran Hung Dao Street N1, Hai Ba Trung District, Hanoi, Vietnam. .,Faculty of Tropical and Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam. .,Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.
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Associations between Vitamin D and Liver Function and Liver Fibrosis in Patients with Biliary Atresia. Gastroenterol Res Pract 2019; 2019:4621372. [PMID: 31781188 PMCID: PMC6875370 DOI: 10.1155/2019/4621372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 08/19/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Objectives To detail the effects of vitamin D (VD) deficiency and assess the relationships between VD deficiency and liver function and liver fibrosis in patients with biliary atresia (BA). Methods In this study, BA patients confirmed by intraoperative cholangiography were enrolled between January 2017 and February 2019. Preoperative serum 25-(OH)D level, liver function, serum biomarker levels of liver fibrosis, and histopathologic features were recorded. Deficiency, insufficiency, and sufficiency of VD were defined as serum 25-(OH)D concentrations of <10, 10-20, and >20 ng/ml, respectively. Associations between serum 25-(OH)D level and liver function and liver fibrosis were analyzed. Results A total of 161 BA infants were included. The median (interquartile range (IQR)) serum 25-(OH)D level in all patients was 7.56 (IQR: 4.48–11.40) ng/ml. The rates of 25-(OH)D deficiency, insufficiency, and sufficiency were 67.1% (108/161), 29.2% (47/161), and 3.7% (6/161), respectively. Serum 25-(OH)D level was negatively correlated with alkaline phosphatase (r = ‐0.232, P = 0.003). After adjusting for age, a decrease in serum 25-(OH)D level was correlated with the increase of the Batts-Ludwig stage score (odds ratio (OR): 0.94, 95% confidence interval (CI): 0.88–0.99; P = 0.028). Serum 25-(OH)D level was also correlated with the N-terminal propeptide of type III procollagen (PIIINP) (r = ‐0.246, P = 0.002). Additionally, PIIINP (P = 0.038) and ALP (P = 0.031) were independently associated with serum 25-(OH)D level. Conclusions VD deficiency was common and inversely correlated with liver fibrosis in BA patients. Furthermore, VD was not correlated with liver function except alkaline phosphatase.
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Lin LY, Bhate K, Forbes H, Smeeth L, Warren-Gash C, Langan S. Vitamin D deficiency or supplementation and the risk of human herpesvirus infections or reactivation: a systematic review protocol. BMJ Open 2019; 9:e031867. [PMID: 31594899 PMCID: PMC6797410 DOI: 10.1136/bmjopen-2019-031867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Human herpesviruses induce lifelong latent infections and may reactivate as the immune system deteriorates. Recent studies have suggested that vitamin D, an essential element of bone health, may have some effect of protecting against infections, but investigations of its potential to prevent herpesvirus infection or reactivation are limited. We will review the current literature examining vitamin D and the risk of herpesvirus infections or reactivation. METHODS AND ANALYSIS Our systematic review will address two research questions: (1) Do deficient/insufficient serum vitamin D levels increase the risk of herpesvirus infections and (2) Does vitamin D supplementation protect against herpesvirus infections? We will include only intervention studies with control groups, cohort studies and case-control studies. We will use subject headings and keywords to search for synonyms of 'vitamin D' and 'herpesviruses' (including herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus and human herpesviruses type 6, 7 and 8) in Medline, Embase, Global Health, Web of Science, Scopus and Cochrane Central Register of Controlled Trials, and the grey literature databases Open Grey, EThOS and BASE from inception to 31 August 2019. References to the included articles and relevant systematic reviews will also be examined. Two reviewers will independently screen the study titles and abstracts, and examine the full texts to decide the final eligibility. They will independently extract data from the studies and assess bias using the Cochrane Collaboration approach. A third researcher will solve any discrepancies. The results will be narratively synthesised; if an adequate number of studies is included and the homogeneity between studies is acceptable, a meta-analysis will be performed. We will assess the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation framework, and display the results in a summary of findings table. ETHICS AND DISSEMINATION Ethical review is not required for a systematic review. We will publish the results in a peer-review journal. Any amendments to the protocol will be recorded in the supplementary section. PROSPERO REGISTRATION NUMBER CRD42019130153.
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Affiliation(s)
- Liang-Yu Lin
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, London, UK
| | - Ketaki Bhate
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, London, UK
| | - Harriet Forbes
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, London, UK
| | - Liam Smeeth
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, London, UK
| | - Charlotte Warren-Gash
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, London, UK
| | - Sinéad Langan
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, London, UK
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Thanapirom K, Suksawatamnuay S, Sukeepaisarnjaroen W, Tangkijvanich P, Thaimai P, Wasitthankasem R, Poovorawan Y, Komolmit P. Genetic associations of vitamin D receptor polymorphisms with advanced liver fibrosis and response to pegylated interferon-based therapy in chronic hepatitis C. PeerJ 2019; 7:e7666. [PMID: 31565578 PMCID: PMC6744935 DOI: 10.7717/peerj.7666] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/13/2019] [Indexed: 12/25/2022] Open
Abstract
Vitamin D receptor (VDR) modulates host immune responses to infections such as hepatitis C virus (HCV) infection, including interferon signaling. This study aimed to investigate the associations of VDR polymorphisms with advanced liver fibrosis and response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. In total, 554 Thai patients with chronic HCV infection treated with a PEG-IFN-based regimen were enrolled. Six single-nucleotide polymorphisms (SNPs) were genotyped: the IL28B C > T (rs12979860) SNP and five VDR SNPs, comprising FokI T > C (rs2228570), BsmI C > T (rs1544410), Tru9I G > A (rs757343), ApaI C > A (rs7975232), and TaqI A > G (rs731236). In total, 334 patients (60.3%) achieved sustained virological response (SVR), and 255 patients (46%) were infected with HCV genotype 1. The bAt (CCA) haplotype, consisting of the BsmI rs1544410 C, ApaI rs7975232 C, and TaqI rs731236 A alleles, was associated with poor response (in terms of lack of an SVR) to PEG-IFN-based therapy. The IL28B rs12979860 CT/TT genotypes (OR = 3.44, 95% CI [2.12–5.58], p < 0.001), bAt haplotype (OR = 2.02, 95% CI [1.04–3.91], p = 0.03), pre-treatment serum HCV RNA (logIU/mL; OR = 1.73, 95% CI [1.31–2.28], p < 0.001), advanced liver fibrosis (OR = 1.68, 95% CI [1.10–2.58], p = 0.02), and HCV genotype 1 (OR = 1.59, 95% CI [1.07–2.37], p = 0.02) independently predicted poor response. Patients with the bAt haplotype were more likely to have poor response compared to patients with other haplotypes (41.4% vs 21.9%, p = 0.03). The FokI rs2228570 TT/TC genotypes (OR = 1.63, 95% CI [1.06–2.51], p = 0.03) and age ≥55 years (OR = 2.25; 95% CI [1.54–3.32], p < 0.001) were independently associated with advanced liver fibrosis, assessed based on FIB-4 score >3.25. VDR polymorphisms were not associated with pre-treatment serum HCV RNA. In Thai patients with chronic HCV infection, the bAt haplotype is associated with poor response to PEG-IFN-based therapy, and the FokI rs2228570 TT/TC genotypes are risk factors for advanced liver fibrosis.
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Affiliation(s)
- Kessarin Thanapirom
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Chulalongkorn University, Liver Fibrosis and Cirrhosis Research Unit, Bangkok, Thailand
| | - Sirinporn Suksawatamnuay
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Chulalongkorn University, Liver Fibrosis and Cirrhosis Research Unit, Bangkok, Thailand
| | - Wattana Sukeepaisarnjaroen
- Department of Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Gastroenterology unit, Khon Kaen, Thailand
| | - Pisit Tangkijvanich
- Faculty of Medicine, Chulalongkorn University, Department of Biochemistry, Bangkok, Thailand
| | - Panarat Thaimai
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Chulalongkorn University, Liver Fibrosis and Cirrhosis Research Unit, Bangkok, Thailand
| | - Rujipat Wasitthankasem
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Center of Excellence in Clinical Virology, Bangkok, Thailand
| | - Yong Poovorawan
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Center of Excellence in Clinical Virology, Bangkok, Thailand
| | - Piyawat Komolmit
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Chulalongkorn University, Liver Fibrosis and Cirrhosis Research Unit, Bangkok, Thailand
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