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Muallem A, Kandel L, Ackerman Z. Prognosis of Cirrhotic Patients After Osteoporotic Femoral Neck Fracture. J Clin Med 2024; 13:6701. [PMID: 39597844 PMCID: PMC11595005 DOI: 10.3390/jcm13226701] [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: 09/30/2024] [Revised: 11/01/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
Introduction and Objectives: Osteoporotic hip fractures in cirrhotic subjects are associated with increased post-fracture mortality. Our aim was to identify unfavorable factors that were associated with increased post-fracture mortality. Patients and Methods: We employed a retrospective evaluation of the short- and long-term prognosis of cirrhotic patients that were admitted with a hip fracture to our institution. Results: A total of 77 cirrhotic and 81 control patients were included. The majority of the patients who died either during the initial three months or during one year of follow-up after the hip fracture were cirrhotic. The patients that did not survive the three-month period suffered from decompensated cirrhosis. The variables that were associated upon multivariate analysis with increased one-year all-cause mortality in both the control and cirrhotic patients were the presence of either cirrhosis, congestive heart failure or low hemoglobin levels upon admission. The variables that were associated upon univariate analysis with increased one-year all-cause mortality only in the cirrhotic patients were the patient's age, the presence of hepatic encephalopathy, as well as the levels of serum albumin, PT (in %) and FIB-4. Our multivariate analysis disclosed that the admission level of PT (in %) was the only parameter that was associated with one-year all-cause mortality among the cirrhotic patients (adjusted OR 0.962, CI: 0.928-0.996, p = 0.029). Conclusions: Patients with decompensated cirrhosis are at an increased risk of dying during the first year after an osteoporotic hip fracture. Cirrhotic patients with osteoporosis who are at risk of hip fractures should be identified and measures to prevent this complication should be implemented.
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Affiliation(s)
- Aviya Muallem
- Department of Orthopedic Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel; (A.M.); (L.K.)
- Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Leonid Kandel
- Department of Orthopedic Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel; (A.M.); (L.K.)
| | - Zvi Ackerman
- Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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Oliveria decumbens Extract Exhibits Hepatoprotective Effects Against Bile Duct Ligation-Induced Liver Injury in Rats by Reducing Oxidative Stress. HEPATITIS MONTHLY 2023. [DOI: 10.5812/hepatmon-131160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Cholestasis is described as a disease in which bile flow from the liver is reduced or stopped, and due to its oxidative effects, irreversible consequences may occur. Due to the remarkable antioxidant properties of Oliveria decumbens (OD) and the contribution of oxidants to the progression of bile duct ligation (BDL)-induced cholestasis, Objectives: This research aimed to examine how the OD ethanolic extract affected liver damage and oxidant-antioxidant balance markers in BDL-induced cholestasis. Methods: Forty male Wistar rats weighing 200 - 250 g were used. Cholestasis was induced using the BDL approach. The rats were categorized into four groups: Group 1, sham control (SC); group 2, cholestatic; group 3, SC + OD; and group 4, cholestatic + OD. A dose of OD ethanolic extract was administered orally (500 mg/kg/day) to rats for seven days. Seven days following surgery, the rats’ blood samples were collected; after sacrifice, a part of the liver tissue was isolated. A histopathological examination was performed, while the rest was stored at -70°C in liquid nitrogen. Heparin-containing tubes were used to gather blood samples. In plasma and hepatic tissue, biochemical tests, histopathological evaluations, and oxidative stress markers staining levels were performed. Results: Our findings showed that OD could effectively reduce liver injury by reducing the activity of liver function enzymes (AST and ALP). At the same time, it did not affect total bilirubin and protein. Bile duct ligation-induced hepatic markers of protein oxidation (PCO) and reactive nitrogen species (NO) were significantly decreased by OD, and it also promoted liver antioxidant capacity by enhancing superoxide dismutase (SOD) activities. Moreover, OD treatment prevented liver bile duct proliferative changes in histopathologic analysis. Conclusions: Our study confirmed that OD exerts substantial hepatoprotective activities against BDL-induced cholestasis by improving liver damage markers and regulating oxidative stress. It may be a beneficial therapeutic agent for managing cholestasis. Bioassay-guided isolation and identification of bioactive OD secondary metabolites can further direct the discovery of potential natural-based drug candidates.
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Shakerinasab N, Azizi M, Mansourian M, Sadeghi H, Salaminia S, Abbasi R, Shahaboddin ME, Doustimotlagh AH. Empagliflozin Exhibits Hepatoprotective Effects Against Bile Duct Ligation-induced Liver Injury in Rats: A Combined Molecular Docking Approach to In Vivo Studies. Curr Pharm Des 2022; 28:3313-3323. [PMID: 36305136 DOI: 10.2174/1381612829666221027112239] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 09/22/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Cholestatic liver damage is a chronic disease caused by dysfunction of the hepaticbiliary system. Oxidative stress and inflammation are essential factors in the pathogenesis of cholestasis. Thus, the current study was designed to examine the effect of empagliflozin on bile duct ligation-induced liver damage in rats. METHODS This study was done on male Wistar rats, which were randomly assigned to the four experimental groups: sham control (SC), bile duct ligation (BDL), SC plus empagliflozin (SC+EMPA) (receiving 10 mg of EMPA orally for 7 days), BDL plus empagliflozin 10 mg/kg (BDL+ EMPA). At the end of the study, the rats were sacrificed, and serum and tissue samples were collected to analyze biochemical parameters, biomarkers of oxidative stress, inflammatory markers, and histopathological changes. The molecular docking technique was performed to elucidate the interaction of EMPA and Cu/Zn-superoxide dismutase (SOD1). RESULTS The results showed that BDL elevated the serum activity of ALT, AST, ALP, and levels of TBIL and TPro. BDL also intensifies the oxidative stress state in rats, which was confirmed by augmenting lipid peroxidation (MDA), protein oxidation (PCO), and altering antioxidant defense parameters through decreased SOD, catalase (CAT), and glutathione peroxidase (GPX) levels. Furthermore, the histopathological changes in the liver demonstrated the aggravation of inflammation and oxidative stress. In contrast, treatment with EMPA has shown anti-inflammatory and anti-oxidant effects by reducing TNF-α and IL-6 pro-inflammatory marker proteins, restoring the antioxidant status (increased SOD and GPX), reducing ALT, AST, ALP, TBIL levels, and protein oxidation, and improving the histopathological alterations through reducing bile duct proliferation, fibrosis, focal and portal inflammation. According to the attained findings, the SOD1 activity can be regulated by the EMPA. Our documentation presents direct evidence at the molecular level related to the ability of EMPA to exert its antioxidant performance through certain measures in a particular molecular route. CONCLUSION The results showed EMPA to have hepatic protective effects in rats against cholestatic liver injury, an effect mediated by its antioxidant and anti-inflammatory properties.
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Affiliation(s)
- Nasrin Shakerinasab
- Department of Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mahdokht Azizi
- Department of Pharmacology, Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mahboubeh Mansourian
- Department of Pharmacology, Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hossein Sadeghi
- Department of Pharmacology, Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Shirvan Salaminia
- Department of Cardiac Surgery, Yasuj University of Medical Science, Yasuj, Iran
| | - Reza Abbasi
- Department of Pediatrics, Yasuj University of Medical Science, Yasuj, Iran
| | | | - Amir Hossein Doustimotlagh
- Department of Pharmacology, Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.,Department of Clinical Biochemistry, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
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Xu X, Wang R, Wu R, Yan W, Shi T, Jiang Q, Shi D. Trehalose reduces bone loss in experimental biliary cirrhosis rats via ERK phosphorylation regulation by enhancing autophagosome formation. FASEB J 2020; 34:8402-8415. [PMID: 32367591 DOI: 10.1096/fj.201902528rrr] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 04/07/2020] [Accepted: 04/13/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Xingquan Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing P.R. China
- Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC) Nanjing University Nanjing P.R. China
| | - Rongliang Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing P.R. China
- Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC) Nanjing University Nanjing P.R. China
| | - Rui Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing P.R. China
- Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC) Nanjing University Nanjing P.R. China
| | - Wenjin Yan
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing P.R. China
- Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC) Nanjing University Nanjing P.R. China
| | - Tianshu Shi
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing P.R. China
- Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC) Nanjing University Nanjing P.R. China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing P.R. China
- Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC) Nanjing University Nanjing P.R. China
| | - Dongquan Shi
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing P.R. China
- Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC) Nanjing University Nanjing P.R. China
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Danford CJ, Ezaz G, Trivedi HD, Tapper EB, Bonder A. The Pharmacologic Management of Osteoporosis in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis. J Clin Densitom 2020; 23:223-236. [PMID: 31146965 DOI: 10.1016/j.jocd.2019.05.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/06/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Osteoporosis is a common complication of primary biliary cholangitis (PBC) yet evidence for effective therapy is lacking. We sought to review all randomized controlled trials evaluating pharmacotherapy against placebo or no intervention for treatment of osteoporosis in PBC. METHODOLOGY A comprehensive database search was conducted from inception through 29 March 2017. The primary outcome was incidence of fractures; secondary outcomes were change in bone mineral density (BMD) and adverse events. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same drug class. RESULTS We identified 11 randomized controlled trials evaluating bisphosphonates (3), hormone replacement therapy (2), ursodeoxycholic acid (1), obeticholic acid (1), cyclosporin A (1), vitamin K (1), calcitriol (1), and sodium fluoride (1). No intervention significantly reduced fractures compared to control. Although significant improvement in BMD was seen in one study with alendronate, a third-generation bisphosphonate, no significant improvement was seen on pooled analysis of all bisphosphonates including first-generation bisphosphonates (standard mean difference 0.41, p = 0.68). On pooled analysis, hormone replacement therapy modestly improved lumbar BMD (standard mean difference 0.69, p = 0.02), but with significantly increased adverse events (odds ratio 8.82, p = 0.01). CONCLUSIONS There is a lack of high-quality evidence supporting the efficacy of any treatment of osteoporosis in PBC. This may be explained by lack of power in the included studies. However, our current understanding of PBC-related osteoporosis indicates that it results from decreased bone formation, which may explain the attenuated effect of traditional antiresorptive agents. Future studies should investigate newer anabolic bone agents.
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Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Ghideon Ezaz
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Danford CJ, Trivedi HD, Bonder A. Bone Health in Patients With Liver Diseases. J Clin Densitom 2020; 23:212-222. [PMID: 30744928 DOI: 10.1016/j.jocd.2019.01.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 12/19/2022]
Abstract
Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.
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Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA.
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Trivedi HD, Danford CJ, Goyes D, Bonder A. Osteoporosis in Primary Biliary Cholangitis: Prevalence, Impact and Management Challenges. Clin Exp Gastroenterol 2020; 13:17-24. [PMID: 32021374 PMCID: PMC6970242 DOI: 10.2147/ceg.s204638] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 12/31/2019] [Indexed: 12/11/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic condition associated with symptoms that directly impact the quality of life in those afflicted with the disease. In addition to pruritus and fatigue, patients with PBC may develop metabolic bone disease from reduced bone density, such as osteopenia and osteoporosis. Osteoporosis increases the risk of fractures, as well as morbidity and mortality. The prevalence of osteoporosis in PBC is expected to increase in conjunction with the rising prevalence of PBC as a whole. Timely diagnosis, prevention and management of osteoporosis are crucial in order to optimize the quality of life. There is a paucity of data evaluating the management of osteoporosis in PBC. The optimal timing for diagnosis and monitoring is not yet established and is guided by expert opinion. National guidelines recommend screening for osteoporosis at the time of diagnosis of PBC. Monitoring strategies are based on results of initial screening and individual risk factors for bone disease. Identifying reduced bone density is imperative to institute timely preventive and treatment strategies. However, treatment remains challenging as efficacious therapies are currently lacking. The data on treatment of osteoporosis in PBC are mostly extrapolated from postmenopausal osteoporosis literature. However, this data has not directly translated to useful treatment strategies for PBC-related osteoporosis, partly because of the different pathophysiological mechanisms of the two diseases. The lack of useful preventive measures and efficacious treatment strategies remains the largest pitfall that challenges the management of patients with PBC. In this review, we comprehensively outline the epidemiology, clinical implications and challenges, as well as management strategies of PBC-related osteoporosis.
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Affiliation(s)
- Hirsh D Trivedi
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christopher J Danford
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Daniela Goyes
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alan Bonder
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Hepatic Osteodystrophy-Molecular Mechanisms Proposed to Favor Its Development. Int J Mol Sci 2019; 20:ijms20102555. [PMID: 31137669 PMCID: PMC6566554 DOI: 10.3390/ijms20102555] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/14/2019] [Accepted: 05/22/2019] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with chronic liver diseases (CLD) show altered bone metabolism. Depending on the etiology, this manifests in a severe osteoporosis in up to 75% of the affected patients. Due to high prevalence, the generic term hepatic osteodystrophy (HOD) evolved, describing altered bone metabolism, decreased bone mineral density, and deterioration of bone structure in patients with CLD. Once developed, HOD is difficult to treat and increases the risk of fragility fractures. Existing fractures affect the quality of life and, more importantly, long-term prognosis of these patients, which presents with increased mortality. Thus, special care is required to support the healing process. However, for early diagnosis (reduce fracture risk) and development of adequate treatment strategies (support healing of existing fractures), it is essential to understand the underlying mechanisms that link disturbed liver function with this bone phenotype. In the present review, we summarize proposed molecular mechanisms favoring the development of HOD and compromising the healing of associated fractures, including alterations in vitamin D metabolism and action, disbalances in transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signaling with histone deacetylases (HDACs) as secondary regulators, as well as alterations in the receptor activator of nuclear factor kappa B ligand (RANKL)–osteoprotegerin (OPG) system mediated by sclerostin. Based on these mechanisms, we give an overview on the limitations of early diagnosis of HOD with established serum markers.
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Merli M, Berzigotti A, Zelber-Sagi S, Dasarathy S, Montagnese S, Genton L, Plauth M, Parés A. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol 2019; 70:172-193. [PMID: 30144956 PMCID: PMC6657019 DOI: 10.1016/j.jhep.2018.06.024] [Citation(s) in RCA: 631] [Impact Index Per Article: 105.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 06/28/2018] [Indexed: 12/11/2022]
Abstract
A frequent complication in liver cirrhosis is malnutrition, which is associated with the progression of liver failure, and with a higher rate of complications including infections, hepatic encephalopathy and ascites. In recent years, the rising prevalence of obesity has led to an increase in the number of cirrhosis cases related to non-alcoholic steatohepatitis. Malnutrition, obesity and sarcopenic obesity may worsen the prognosis of patients with liver cirrhosis and lower their survival. Nutritional monitoring and intervention is therefore crucial in chronic liver disease. These Clinical Practice Guidelines review the present knowledge in the field of nutrition in chronic liver disease and promote further research on this topic. Screening, assessment and principles of nutritional management are examined, with recommendations provided in specific settings such as hepatic encephalopathy, cirrhotic patients with bone disease, patients undergoing liver surgery or transplantation and critically ill cirrhotic patients.
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Danford CJ, Trivedi HD, Papamichael K, Tapper EB, Bonder A. Osteoporosis in primary biliary cholangitis. World J Gastroenterol 2018; 24:3513-3520. [PMID: 30131657 PMCID: PMC6102495 DOI: 10.3748/wjg.v24.i31.3513] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/11/2018] [Accepted: 07/21/2018] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with multiple debilitating complications. Osteoporosis is a common complication of PBC resulting in frequent fractures and leading to significant morbidity in this population, yet evidence for effective therapy is lacking. We sought to summarize our current understanding of the pathophysiology of osteoporosis in PBC, as well as current and emerging therapies in order to guide future research directions. A complete search with a comprehensive literature review was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, and the Countway Library. Osteoporosis in PBC is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Despite this fundamental difference, current treatment recommendations are based primarily on experience with postmenopausal osteoporosis. Trials specific to PBC-related osteoporosis are small and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in PBC relies on the mitigation of risk factors such as smoking and alcohol use, as well as encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in PBC remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in PBC and summarizes current and emerging therapies.
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Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Konstantinos Papamichael
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Elliot B Tapper
- Department of Hepatology, University of Michigan, Ann Arbor, MI 48109, Unites States
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
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Guañabens N, Parés A. Osteoporosis in chronic liver disease. Liver Int 2018; 38:776-785. [PMID: 29479832 DOI: 10.1111/liv.13730] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/19/2018] [Indexed: 12/15/2022]
Abstract
Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in chronic cholestasis, in addition to non-alcoholic fatty liver disease, haemochromatosis and alcoholism. Mechanisms underlying osteoporosis are poorly understood, but osteoporosis mainly results from low bone formation. In this setting, sclerostin, a key regulator of the Wnt/β-catenin signalling pathway which regulates bone formation, in addition to the effects of the retained substances of cholestasis such as bilirubin and bile acids on osteoblastic cells, may influence the decreased bone formation in chronic cholestasis. Similarly, the damaging effects of iron and alcohol on osteoblastic cells may partially explain bone disease in haemochromatosis and alcoholism. A role for proinflammatory cytokines has been proposed in different conditions. Increased bone resorption may occur in cholestatic women with advanced disease. Low vitamin D, poor nutrition and hypogonadism, may be contributing factors to the full picture of bone disorders in chronic liver disease.
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Affiliation(s)
- Núria Guañabens
- Metabolic Bone Diseases Unit, Department of Rheumatology, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Albert Parés
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
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Doustimotlagh AH, Dehpour AR, Etemad-Moghadam S, Alaeddini M, Ostadhadi S, Golestani A. A study on OPG/RANK/RANKL axis in osteoporotic bile duct-ligated rats and the involvement of nitrergic and opioidergic systems. Res Pharm Sci 2018; 13:239-249. [PMID: 29853933 PMCID: PMC5921404 DOI: 10.4103/1735-5362.228954] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Chronic liver disease (CLD) affects millions of people and its impact on bone loss has become a subject of interest. Nitric oxide and endogenous opioids are suggested to increase during cholestasis/cirrhosis and may impact bone resorption by different mechanisms. The receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL)/osteoprotegerin (OPG) signaling pathway regulates bone resorption, but its role in metabolic bone disease subsequent to CLD is unknown. We aimed to investigate the involvement of nitrergic and opioidergic systems in bone loss relative to the RANK/RANKL/OPG pathway, in bile duct-ligated (BDL) rats. Eighty BDL/sham-operated (SO) rats received injections of 3 mg/kg/day Nω-Nitro-L-arginine methyl ester ± naltrexone (10 mg/kg/day) or saline for 28 days. Plasma bone turnover markers, OPG, RANK, and RANKL along with mRNA expression levels of the latter three were assessed. Plasma bone turnover markers and OPG level increased, but RANKL decreased in the BDL group compared with their SO controls (both: P ≤ 0.05). Administration of naltrexone reduced bone turnover markers and OPG level while increased RANKL content in comparison to BDL rats (P ≤ 0.05). As compared to untreated BDL rats, nitric oxide inhibition showed no effect on bone turnover marker i.e. OPG, RANK, and RANKL levels. BDL significantly increased RANK mRNA, but had no significant effect on RANKL and OPG mRNA expression. The lack of association between plasma levels and quantitative gene expression of RANKL and OPG suggests an indirect function of these markers in BDL rats. Considering that opioid receptor blockage by naltrexone in BDL animals caused a significant decrease in OPG and an increase in RANKL plasma contents, it could be postulated that the opioidergic system may have a regulatory effect on these bone markers.
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Affiliation(s)
- Amir Hossein Doustimotlagh
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, I.R. Iran.,Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Shahroo Etemad-Moghadam
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Mojgan Alaeddini
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Sattar Ostadhadi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran.,Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Abolfazl Golestani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran.,Occupational Sleep Research Center (OSRC), Baharloo Hospital, Tehran University of Medical Sciences, Tehran, I.R. Iran
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13
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Bone health and vitamin D status in alcoholic liver disease. Indian J Gastroenterol 2016; 35:253-9. [PMID: 27246833 DOI: 10.1007/s12664-016-0652-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 03/26/2016] [Indexed: 02/07/2023]
Abstract
Alcohol consumption is harmful to many organs and tissues, including bones, and it leads to osteoporosis. Hepatic osteodystrophy is abnormal bone metabolism that has been defined in patients with chronic liver disease (CLD), including osteopenia, osteoporosis, and osteomalacia. Decreased bone density in patients with CLD results from decreased bone formation or increased bone resorption. The prevalence of osteopenia in alcoholic liver disease (ALD) patients is between 34 % and 48 %, and the prevalence of osteoporosis is between 11 % and 36 %. Cirrhosis is also a risk factor for osteoporosis. The liver has an important role in vitamin D metabolism. Ninety percent of patients with alcoholic liver cirrhosis have vitamin D inadequacy (<80 nmol/L). The lowest serum vitamin D levels were observed in patients with Child-Pugh class C. Bone densitometry is used for the definitive diagnosis of osteoporosis in ALD. There are no specific controlled clinical studies on the treatment of osteoporosis in patients with ALD. Alcohol cessation and abstinence are principal for the prevention and treatment of osteoporosis in ALD patients, and the progression of osteopenia can be stopped in this way. Calcium and vitamin D supplementation is recommended, and associated nutritional deficiencies should also be corrected. The treatment recommendations of osteoporosis in CLD tend to be extended to ALD. Bisphosphonates have been proven to be effective in increasing bone mineral density (BMD) in chronic cholestatic disease and post-transplant patients, and they can be used in ALD patients. Randomized studies assessing the management of CLD-associated osteoporosis and the development of new drugs for osteoporosis may change the future. Here, we will discuss bone quality, vitamin D status, mechanism of bone effects, and diagnosis and treatment of osteoporosis in ALD.
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14
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Vinik Y, Shatz-Azoulay H, Vivanti A, Hever N, Levy Y, Karmona R, Brumfeld V, Baraghithy S, Attar-Lamdar M, Boura-Halfon S, Bab I, Zick Y. The mammalian lectin galectin-8 induces RANKL expression, osteoclastogenesis, and bone mass reduction in mice. eLife 2015; 4:e05914. [PMID: 25955862 PMCID: PMC4424493 DOI: 10.7554/elife.05914] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Accepted: 04/16/2015] [Indexed: 01/20/2023] Open
Abstract
Skeletal integrity is maintained by the co-ordinated activity of osteoblasts, the bone-forming cells, and osteoclasts, the bone-resorbing cells. In this study, we show that mice overexpressing galectin-8, a secreted mammalian lectin of the galectins family, exhibit accelerated osteoclasts activity and bone turnover, which culminates in reduced bone mass, similar to cases of postmenopausal osteoporosis and cancerous osteolysis. This phenotype can be attributed to a direct action of galectin-8 on primary cultures of osteoblasts that secrete the osteoclastogenic factor RANKL upon binding of galectin-8. This results in enhanced differentiation into osteoclasts of the bone marrow cells co-cultured with galectin-8-treated osteoblasts. Secretion of RANKL by galectin-8-treated osteoblasts can be attributed to binding of galectin-8 to receptor complexes that positively (uPAR and MRC2) and negatively (LRP1) regulate galectin-8 function. Our findings identify galectins as new players in osteoclastogenesis and bone remodeling, and highlight a potential regulation of bone mass by animal lectins. DOI:http://dx.doi.org/10.7554/eLife.05914.001 The forces applied to the body during daily activities cause bones to be constantly remodeled, which is essential for keeping them healthy. In most adult organisms, new bone is created at the same rate at which old bone is destroyed. This means that overall bone mass remains the same. But, in diseases such as osteoporosis or bone cancer, bone is destroyed more rapidly than at which new bone is made. This leads to brittle bones that are more likely to fracture. Understanding how to increase the rate of bone renewal might therefore help scientists develop new treatments for bone diseases. Bone is created by cells called osteoblasts and destroyed by other cells called osteoclasts. Both of these types of cells develop from stem cells in the bone marrow. The activity of these cells is controlled by a number of factors, including the matrix of proteins that holds bone together. A group of proteins called galectins are known to act as a bridge between some of the matrix proteins and molecules on the surface of the cells. Vinik et al. took osteoblasts from a mouse skull, grew them in the laboratory, and then exposed them to a galectin protein called galectin-8. This made the osteoblasts release a protein called RANKL, which is known to boost osteoclast activity. When osteoblasts that had been exposed to galectin-8 were grown alongside bone marrow stem cells, more of the stem cells developed into the bone-destroying osteoclasts. Mice that were genetically engineered to produce more galectin-8 than normal mice develop brittle bones, despite also creating new bone at a higher rate than do normal mice. This is because osteoclast activity increases at a greater rate, resulting in an overall loss of bone in these animals. This is similar to what occurs in some individuals with osteoporosis. These experiments therefore suggest that galectin-8 plays an important role in bone remodeling and that it may be a potential target for drugs that treat diseases that weaken bones. DOI:http://dx.doi.org/10.7554/eLife.05914.002
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Affiliation(s)
- Yaron Vinik
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Hadas Shatz-Azoulay
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Alessia Vivanti
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Navit Hever
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Yifat Levy
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Rotem Karmona
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Vlad Brumfeld
- Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel
| | - Saja Baraghithy
- Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - Sigalit Boura-Halfon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Itai Bab
- Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yehiel Zick
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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15
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Osteoporosis in primary biliary cirrhosis of the liver. GASTROENTEROLOGY REVIEW 2014; 9:82-7. [PMID: 25061487 PMCID: PMC4108749 DOI: 10.5114/pg.2014.42502] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Revised: 03/15/2012] [Accepted: 04/02/2012] [Indexed: 12/12/2022]
Abstract
Osteoporosis is a metabolic bone disease associated with a reduction in bone mass and deterioration of bone architecture, leading to increased fragility and subsequent low-trauma fractures in the vertebral column, hip, forearm and other bones. In literature, metabolic bone diseases such as osteoporosis and osteomalacia have been recognised as a complication of chronic liver disease, although the mechanisms of this association remain unclear. An increasing body of research data indicates a strong relationship between osteoporosis and primary biliary cirrhosis (PBC), which mainly results from early diagnosis of the disease, usually when it is still asymptomatic. The incidence of osteoporosis in PBC ranges from 20% to 44% and increases with the progression of the disease. Similarly, the incidence of bone fractures is high in this group of patients (10-20%). In this article, current knowledge on risk factors, pathogenesis, diagnosis and treatment of osteoporosis in PBC is reviewed.
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16
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Derakhshanian H, Ghadbeigi S, Rezaian M, Bahremand A, Javanbakht MH, Golpaie A, Hosseinzadeh P, Tajik N, Dehpour AR. Quercetin improves bone strength in experimental biliary cirrhosis. Hepatol Res 2013; 43:394-400. [PMID: 22882531 DOI: 10.1111/j.1872-034x.2012.01075.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Metabolic bone disorders and reduced bone mass are common complications in patients with biliary cirrhosis. As a result of there being no clear etiology, no specific therapy has been established yet. Previous studies have reported that quercetin, a plant-derived flavonoid, might improve bone quality. The present study was designed to investigate the effect of quercetin on bone strength of biliary cirrhotic rats. METHODS Twenty-four male Sprague-Dawley rats aged 6-7 months were randomized into three groups of eight. One group served as control (sham operated), while the other two groups underwent a complete bile duct ligation (BDL). Four weeks after the operation, serum bilirubin, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase were measured in animal blood samples to confirm the occurrence of cirrhosis in the BDL rats. Then, one of the BDL groups received placebo and the other one was injected once a day with 150 µmol/kg of quercetin for 4 weeks. At the end of the study, femora were removed and tested for bone strength and histomorphometric parameters. The serum levels of osteocalcin, C-terminal cross-linked telopeptide of type I collagen, calcium and phosphorus were determined as bone turnover markers. RESULTS Femur breaking strength was dramatically lower in the BDL group compared with control. However, receiving quercetin could reverse the deteriorating effect of cirrhosis on bone strength of BDL rats. Quercetin could noticeably elevate osteocalcin as a bone formation marker. CONCLUSION These data suggest that quercetin can significantly improve bone strength particularly due to increasing bone formation in biliary cirrhosis.
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Affiliation(s)
- Hoda Derakhshanian
- Department of Nutrition and Biochemistry, School of Public Health Department of Medicinal Chemistry, School of Pharmacy Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences Department of Histology, School of Veterinary Medicine, University of Tehran, Tehran Department of Nutrition and Biochemistry, The International Campus, Tehran University of Medical Sciences, Kish, Iran
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17
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Guañabens N, Parés A. Osteoporosis en la cirrosis hepática. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:411-20. [DOI: 10.1016/j.gastrohep.2012.01.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Accepted: 01/31/2012] [Indexed: 12/22/2022]
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18
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López-Larramona G, Lucendo AJ, González-Castillo S, Tenias JM. Hepatic osteodystrophy: An important matter for consideration in chronic liver disease. World J Hepatol 2011; 3:300-7. [PMID: 22216370 PMCID: PMC3246548 DOI: 10.4254/wjh.v3.i12.300] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 09/21/2011] [Accepted: 11/07/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatic osteodystrophy (HO) is the generic term defining the group of alterations in bone mineral metabolism found in patients with chronic liver disease. This paper is a global review of HO and its main pathophysiological, epidemiological and therapeutic aspects. Studies examining the most relevant information concerning the prevalence, etiological factors, diagnostic and therapeutic aspects involved in HO were identified by a systematic literature search of the PubMed database. HO generically defines overall alterations in bone mineral density (BMD) (osteoporosis or osteopenia) which appear as a possible complication of chronic liver disease. The origin of HO is multifactorial and its etiology and severity vary in accordance with the underlying liver disease. Its exact prevalence is unknown, but different studies estimate that it could affect from 20% to 50% of patients. The reported mean prevalence of osteoporosis ranges from 13%-60% in chronic cholestasis to 20% in chronic viral hepatitis and 55% in viral cirrhosis. Alcoholic liver disease is not always related to osteopenia. HO has been commonly studied in chronic cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis). Several risk factors and pathogenic mechanisms have been associated with the loss of BMD in patients with chronic liver disease. However, little information has been discovered in relationship to most of these mechanisms. Screening for osteopenia and osteoporosis is recommended in advanced chronic liver disease. There is a lack of randomized studies assessing specific management for HO.
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Affiliation(s)
- Germán López-Larramona
- Germán López-Larramona, Department of Internal Medicine, Hospital General de Tomelloso, 13700 Ciudad Real, Spain
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19
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Guañabens N, Parés A. Management of osteoporosis in liver disease. Clin Res Hepatol Gastroenterol 2011; 35:438-45. [PMID: 21546334 DOI: 10.1016/j.clinre.2011.03.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 03/16/2011] [Indexed: 02/04/2023]
Abstract
Osteoporosis resulting in a high risk for fracture is a common complication in patients with liver disease, particularly in those with chronic cholestasis and with end-stage cirrhosis. The pathogenesis of bone loss in liver patients is poorly understood but it mainly results from low bone formation as a consequence of cholestasis or the harmful effects of alcohol or iron on osteoblasts. Increased bone resorption has also been described in cholestatic women with advanced disease. The management of bone disease in liver patients is addressed to reduce or avoid the risk factors for osteoporosis and fracture. Bisphosphonates associated with supplements of calcium and vitamin D are safe and effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation, though no clear achievements in descreasing the incidence of fractures have been described, probably because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future.
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Affiliation(s)
- Núria Guañabens
- Liver Unit, Department of Rheumatology, Hospital Clínic, CIBERhed, University of Barcelona, Barcelona, Spain
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20
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Miheller P, Lakatos PL, Tóth M. Bone Homeostasis in Intestinal Disorders. Clin Rev Bone Miner Metab 2010. [DOI: 10.1007/s12018-010-9069-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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21
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Guañabens N, Parés A. Liver and bone. Arch Biochem Biophys 2010; 503:84-94. [PMID: 20537977 DOI: 10.1016/j.abb.2010.05.030] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2010] [Revised: 05/24/2010] [Accepted: 05/26/2010] [Indexed: 02/06/2023]
Abstract
Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in cases with chronic cholestasis, hemochromatosis and alcohol abuse. The problem is more critical in transplant patients when bone loss is accelerated during the period immediately after transplantation, leading to a greater incidence of fractures. Advanced age, low body mass index and severity of the liver disease are the main risk factors for bone disease in patients with cholestasis. Mechanisms underlying osteoporosis in chronic liver disease are complex and poorly understood, but osteoporosis mainly results from low bone formation, related to the effects of retained substances of cholestasis, such as bilirubin and bile acids, or to the effects of alcohol on osteoblastic cells. Increased bone resorption has also been described in cholestatic women with advanced disease. Although there is no specific treatment, bisphosphonates associated with supplements of calcium and vitamin D are effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation. The outcome in reducing the incidence of fractures has not been adequately demonstrated essentially because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future.
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Affiliation(s)
- Núria Guañabens
- Department of Rheumatology, University of Barcelona, Barcelona, Spain.
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Abstract
Osteoporosis is a common complication of many types of liver disease. Research into the pathogenesis of osteoporosis has revealed that the mechanisms of bone loss differ between different types of liver disease. This Review summarizes our current understanding of osteoporosis associated with liver disease and the new advances that have been made in this field. The different mechanisms by which cholestatic and parenchymal liver disease can lead to reduced bone mass, the prevalence of osteopenia and osteoporosis in patients with early and advanced liver disease, and the influence of osteoporotic fractures on patient survival are discussed along with the advances in our understanding of the molecular pathways associated with bone loss. The role of the CSF1-RANKL system and that of the liver molecule, oncofetal fibronectin, a protein that has traditionally been viewed as an extracellular matrix protein are also discussed. The potential impact that these advances may have for the treatment of osteoporosis associated with liver disease is also reviewed.
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Pereira FA, Facincani I, Jorgetti V, Ramalho LNZ, Volpon JB, Dos Reis LM, de Paula FJA. Etiopathogenesis of hepatic osteodystrophy in Wistar rats with cholestatic liver disease. Calcif Tissue Int 2009; 85:75-83. [PMID: 19424739 DOI: 10.1007/s00223-009-9249-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2009] [Accepted: 03/31/2009] [Indexed: 12/13/2022]
Abstract
The pathophysiology of hepatic osteodystrophy (HO) remains poorly understood. Our aim was to evaluate bone histomorphometry, biomechanical properties, and the role of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) system in the onset of this disorder. Forty-six male Wistar rats were divided into two groups: sham-operated (SO, n = 23) and bile duct-ligated (BDL, n = 23). Rats were killed on day 30 postoperatively. Immunohistochemical expression of IGF-I and GH receptor was determined in liver tissue and in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia, and the right femur was used for biomechanical analysis. The maximal force at fracture and the stiffness of the mid-shaft femur were, respectively, 53% and 24% lower in BDL compared to SO. Histomorphometric measurements showed low cancellous bone volume and decreased cancellous bone connectivity in BDL, compatible with osteoporosis. This group also showed increased mineralization lag time, indicating disturbance in bone mineralization. Serum levels of IGF-I were lower in BDL (basal 1,816 +/- 336 vs. 30 days 1,062 +/- 191 ng/ml, P < 0.0001). BDL also showed higher IGF-I expression in the liver tissue but lower IGF-I and GH receptor expression in growth plate cartilage than SO. Osteoporosis is the most important feature of HO; BDL rats show striking signs of reduced bone volume and decreased bone strength, as early as after 1 month of cholestasis. The endocrine and autocrine-paracrine IGF-I systems are deeply affected by cholestasis. Further studies will be necessary to establish their role in the pathogenesis of HO.
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Affiliation(s)
- F A Pereira
- Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil
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Sangild PT, Mei J, Fowden AL, Xu RJ. The prenatal porcine intestine has low transforming growth factor-beta ligand and receptor density and shows reduced trophic response to enteral diets. Am J Physiol Regul Integr Comp Physiol 2009; 296:R1053-62. [DOI: 10.1152/ajpregu.90790.2008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Transforming growth factor-beta (TGF-β) plays a role in enterocyte proliferation control, cell differentiation, and immune regulation via binding to specific TGF-β receptors (TGF-β R) in the intestinal epithelium. Endogenous TGF-β production is low in the intestine during the perinatal period, but some exogenous TGF-β ligands are supplied by amniotic fluid intake in the fetus and by colostrum ingestion in the neonate. It is not clear, however, whether luminal TGF-β receptors are present and functional at this critical time. We studied intestinal TGF-β receptors by immunohistochemistry during the last 20% of gestation in pigs and in chronically catheterized fetuses following exposure to colostrum, milk, and amniotic fluid (control). In fetal pigs, the TGF-β Rs were predominantly localized to the crypt epithelium, but staining intensity increased markedly just before term and shifted to the villous epithelium in newborn pigs, concurrently with marked increases in villous heights and crypt depths (+100–200%, P < 0.05). In contrast to previous observations in term newborn pigs, fetal pigs did not show any milk-induced change in TGF-β receptor densities or localization, although a moderate increase in villous height was observed, relative to control (+25–50%, P < 0.05). We conclude that intestinal TGF-β receptor density and localization are immature and unresponsive to TGF-β containing milk diets in prenatal pigs. Immaturity of TGF-β-mediated immune regulation may play a role in the increased sensitivity of preterm neonates to diet-induced intestinal inflammatory disorders.
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25
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Hamdani G, Gabet Y, Rachmilewitz D, Karmeli F, Bab I, Dresner-Pollak R. Dextran sodium sulfate-induced colitis causes rapid bone loss in mice. Bone 2008; 43:945-50. [PMID: 18675386 DOI: 10.1016/j.bone.2008.06.018] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2008] [Revised: 06/17/2008] [Accepted: 06/25/2008] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Osteopenia is a common complication of human inflammatory bowel disease (IBD). We evaluated the contribution of colonic inflammation to osteopenia and its mechanism in a murine colitis model. METHODS Colitis was induced by adding dextran sodium sulfate (DSS) to the drinking water for 2 weeks to nine-week-old Balb/C male mice. 5% DSS was added on the first week and was reduced to 2.5% on the second week. Age- and sex-matched Balb/C mice served as the control group. Indices of femoral bone mass and architecture were determined by micro computed tomography (muCT). Bone formation parameters and osteoclast number were determined by dynamic histomorphometry. The degree of colonic inflammation was assessed by a clinical disease activity index, and colonic mucosal myeloperoxidase activity. RESULTS DSS-treated mice exhibited a significantly lower bone mass compared to controls as indicated by decreased trabecular bone volume (BV/TV) of 32%. This reduction was accompanied by decreased trabecular number (23%) and connectivity density (37%) compared to the controls. No changes were observed in cortical bone indices. Osteopenia resulted from suppressed bone formation, as indicated by decreased trabecular double-labeled surface (dL%) of 90%, mineralizing surface (MS) of 62%, and bone formation rate (BFR) of 67%, and increased bone resorption as indicated by a 34% increase in osteoclast number in DSS-treated mice compared to the controls. Myeloperoxidase activity inversely correlated with trabecular BV/TV (r=-0.67, p=0.02), trabecular number (r=-0.86, p=0.0008) and connectivity density (r=-0.63, p=0.03). Myeloperoxidase activity inversely correlated with the bone formation indices: dL%, MS, and BFR (r=-0.79, p=0.007, r=-0.84, p=0.002, r=-0.83, p=0.003, respectively). CONCLUSIONS DSS-induced colitis is associated with reduced femoral bone mass and altered micro architecture, which results from suppressed bone formation and increased bone resorption. The decrease in indices of bone mass, structure and formation are directly linked to the degree of colonic mucosal inflammation. DSS-induced colitis can be used to study pharmacological interventions for bone loss in colitis.
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Affiliation(s)
- Gilad Hamdani
- Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
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