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Peček J, Fister P, Homan M. Abernethy syndrome in Slovenian children: Five case reports and review of literature. World J Gastroenterol 2020; 26:5731-5744. [PMID: 33088165 PMCID: PMC7545390 DOI: 10.3748/wjg.v26.i37.5731] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/11/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Abernethy syndrome is a congenital vascular anomaly in which the portal blood completely or partially bypasses the liver through a congenital portosystemic shunt. Although the number of recognized and reported cases is gradually increasing, Abernethy syndrome is still a rare disease entity, with an estimated prevalence between 1 per 30000 to 1 per 50000 cases. With this case series, we aimed to contribute to the growing knowledge of potential clinical presentations, course and complications of congenital portosystemic shunts (CPSS) in children.
CASE SUMMARY Five children are presented in this case series: One female and four males, two with an intrahepatic CPSS and three with an extrahepatic CPSS. The first patient, who was diagnosed with an intrahepatic CPSS, presented with gastrointestinal bleeding, abdominal pain and hyperammonaemia at six years of age. He underwent a percutaneous embolization of his shunt and has remained asymptomatic ever since. The second patient presented with direct hyperbilirubinemia in the neonatal period and his intrahepatic CPSS later spontaneously regressed. The third patient had pulmonary hypertension and hyperammonaemia due to complete portal vein agenesis and underwent liver transplantation at five years of age. The fourth patient was diagnosed immediately after birth, when evaluated due to another congenital vascular anomaly, and the last patient presented as a teenager with recurrent bone fractures associated with severe osteoporosis. In addition, the last two patients are characterised by benign liver nodules; however, they are clinically stable on symptomatic therapy.
CONCLUSION Abernethy syndrome is a rare anomaly with diverse clinical features, affecting almost all organ systems and presenting at any age.
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Affiliation(s)
- Jerneja Peček
- Division of Paediatrics, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia
| | - Petja Fister
- Department of Neonatology, Division of Paediatrics, University Medical Centre Ljubljana; Faculty of medicine, University of Ljubljana, Ljubljana 1000, Slovenia
| | - Matjaž Homan
- Department of Gastroenterology, Hepatology and Nutrition, Division of Paediatrics, University Medical Centre Ljubljana; Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
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Nussler AK, Wildemann B, Freude T, Litzka C, Soldo P, Friess H, Hammad S, Hengstler JG, Braun KF, Trak-Smayra V, Godoy P, Ehnert S. Chronic CCl4 intoxication causes liver and bone damage similar to the human pathology of hepatic osteodystrophy: a mouse model to analyse the liver-bone axis. Arch Toxicol 2014; 88:997-1006. [PMID: 24381012 DOI: 10.1007/s00204-013-1191-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 12/18/2013] [Indexed: 12/20/2022]
Abstract
Patients with chronic liver diseases frequently exhibit decreased bone mineral densities (BMD), which is defined as hepatic osteodystrophy (HOD). HOD is a multifactorial disease whose regulatory mechanisms are barely understood. Thus, an early diagnosis and therapy is hardly possible. Therefore, the aim of our study consisted in characterizing a mouse model reflecting the human pathomechanism. Serum samples were collected from patients with chronic liver diseases and 12-week old C57Bl6/N mice after 6-week treatment with carbon tetrachloride (CCl4). Repetitive injections of CCl4 induced liver damage in mice, resembling liver fibrosis in patients, as assessed by serum analysis and histological staining. Although CCl4 did not affect primary osteoblast cultures, μCT analysis revealed significantly decreased BMD, bone volume, trabecular number and thickness in CCl4-treated mice. In both HOD patients and CCl4-treated mice, an altered vitamin D metabolism with decreased CYP27A1, CYP2R1, vitamin D-binding protein GC and increased 7-dehydrocholesterol reductase hepatic gene expression, results in decreased 25-OH vitamin D serum levels. Moreover, both groups exhibit excessively high active transforming growth factor-beta (TGF-β) serum levels, inhibiting osteoblast function in vitro. Summarizing, our mouse model presents possible mediators of HOD, e.g. altered vitamin D metabolism and increased active TGF-β. Liver damage and significant changes in bone structure and mineralization are already visible by μCT analysis after 6 weeks of CCl4 treatment. This fast response and easy transferability makes it an ideal model to investigate specific gene functions in HOD.
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Affiliation(s)
- Andreas K Nussler
- Siegfried Weller Institute for Trauma Research, Eberhard-Karls-Universität Tübingen, Schnarrenbergstraße 95, 72076, Tübingen, Germany,
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3
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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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Gaudio A, Pennisi P, Muratore F, Bertino G, Ardiri A, Pulvirenti I, Tringali G, Fiore CE. Reduction of volumetric bone mineral density in postmenopausal women with hepatitis C virus-correlated chronic liver disease: a peripheral quantitative computed tomography (pQCT) study. Eur J Intern Med 2012; 23:656-60. [PMID: 22892442 DOI: 10.1016/j.ejim.2012.05.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2012] [Revised: 04/23/2012] [Accepted: 05/13/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND The prevalence of osteoporosis in chronic liver disease (CLD) varies considerably among the studies, depending on patient selection and diagnostic criteria. We aimed to measure bone turnover markers and volumetric bone mineral density (BMD) in a group of postmenopausal women with CLD using both dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), in comparison with age-matched healthy subjects. METHODS Thirty-five postmenopausal patients with HCV-correlated CLD and 35 healthy postmenopausal women, as controls, underwent a DXA scan at lumbar and femoral level and a pQCT measurement of the nondominant forearm. Serum concentrations of biochemical markers relevant to bone turnover were also measured. RESULTS Patients showed no differences in DXA values either at lumbar or femoral level compared to controls. On the contrary, pQCT geometrical (cortical cross-sectional area) and volumetric (total and trabecular volumetric BMD) parameters were significantly reduced in the CLD women. Also the Strength-Strain Index (SSI), an estimate of diaphyseal bone resistance to bending and torsion, was significantly lower in patients than in controls. Patients with CLD presented an unbalanced bone turnover, with increased bone resorption markers. CONCLUSIONS The bone geometrical and volumetric parameters measured in our CLD postmenopausal women, by pQCT, show a reduced bone mineral quality and stiffness. Conversely, DXA-measurements seem unable to appreciate the bone alterations in these patients. This would encourage further studies to validate pQCT analysis as a diagnostic tool for a correct estimate of bone involvement in CLD.
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Affiliation(s)
- Agostino Gaudio
- Department of Internal Medicine, University of Catania, Via Plebiscito 628, 95124 Catania Italy
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5
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Mechanistic investigations on the etiology of Risperdal® Consta®-induced bone changes in female Wistar Hannover rats. Toxicology 2012; 299:90-8. [DOI: 10.1016/j.tox.2012.05.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 05/04/2012] [Accepted: 05/05/2012] [Indexed: 11/21/2022]
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Clinical manifestations of portal hypertension. Int J Hepatol 2012; 2012:203794. [PMID: 23024865 PMCID: PMC3457672 DOI: 10.1155/2012/203794] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 07/20/2012] [Accepted: 07/25/2012] [Indexed: 02/07/2023] Open
Abstract
The portal hypertension is responsible for many of the manifestations of liver cirrhosis. Some of these complications are the direct consequences of portal hypertension, such as gastrointestinal bleeding from ruptured gastroesophageal varices and from portal hypertensive gastropathy and colopathy, ascites and hepatorenal syndrome, and hypersplenism. In other complications, portal hypertension plays a key role, although it is not the only pathophysiological factor in their development. These include spontaneous bacterial peritonitis, hepatic encephalopathy, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and portopulmonary hypertension.
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Yang F, Priester S, Onori P, Venter J, Renzi A, Franchitto A, Munshi MK, Wise C, Dostal DE, Marzioni M, Saccomanno S, Ueno Y, Gaudio E, Glaser S. Castration inhibits biliary proliferation induced by bile duct obstruction: novel role for the autocrine trophic effect of testosterone. Am J Physiol Gastrointest Liver Physiol 2011; 301:G981-91. [PMID: 21903763 PMCID: PMC3233786 DOI: 10.1152/ajpgi.00061.2011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Increased cholangiocyte growth is critical for the maintenance of biliary mass during liver injury by bile duct ligation (BDL). Circulating levels of testosterone decline following castration and during cholestasis. Cholangiocytes secrete sex hormones sustaining cholangiocyte growth by autocrine mechanisms. We tested the hypothesis that testosterone is an autocrine trophic factor stimulating biliary growth. The expression of androgen receptor (AR) was determined in liver sections, male cholangiocytes, and cholangiocyte cultures [normal rat intrahepatic cholangiocyte cultures (NRICC)]. Normal or BDL (immediately after surgery) rats were treated with testosterone or antitestosterone antibody or underwent surgical castration (followed by administration of testosterone) for 1 wk. We evaluated testosterone serum levels; intrahepatic bile duct mass (IBDM) in liver sections of female and male rats following the administration of testosterone; and secretin-stimulated cAMP levels and bile secretion. We evaluated the expression of 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3, the enzyme regulating testosterone synthesis) in cholangiocytes. We evaluated the effect of testosterone on the proliferation of NRICC in the absence/presence of flutamide (AR antagonist) and antitestosterone antibody and the expression of 17β-HSD3. Proliferation of NRICC was evaluated following stable knock down of 17β-HSD3. We found that cholangiocytes and NRICC expressed AR. Testosterone serum levels decreased in castrated rats (prevented by the administration of testosterone) and rats receiving antitestosterone antibody. Castration decreased IBDM and secretin-stimulated cAMP levels and ductal secretion of BDL rats. Testosterone increased 17β-HSD3 expression and proliferation in NRICC that was blocked by flutamide and antitestosterone antibody. Knock down of 17β-HSD3 blocks the proliferation of NRICC. Drug targeting of 17β-HSD3 may be important for managing cholangiopathies.
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Affiliation(s)
- Fuquan Yang
- Department of Medicine, Division of 1Gastroenterology and ,6Department of Hepatobiliary Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, China;
| | - Sally Priester
- Department of Medicine, Division of 1Gastroenterology and ,3Research & Education, Scott & White,
| | - Paolo Onori
- 7Experimental Medicine, University of L'Aquila, L'Aquila;
| | - Julie Venter
- Department of Medicine, Division of 1Gastroenterology and
| | - Anastasia Renzi
- Department of Medicine, Division of 1Gastroenterology and ,10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome;
| | - Antonio Franchitto
- 10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome; ,11Institute of Food and Radiation Safety, Dhaka, Bangladesh
| | - Md Kamruzzaman Munshi
- Department of Medicine, Division of 1Gastroenterology and ,11Institute of Food and Radiation Safety, Dhaka, Bangladesh
| | - Candace Wise
- Department of Medicine, Division of 1Gastroenterology and
| | - David E. Dostal
- 2Molecular Cardiology, Scott & White and Texas A&M Health Science Center, College of Medicine, ,5Central Texas Veterans Health Care System, Temple, Texas;
| | - Marco Marzioni
- 8Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy,
| | - Stefania Saccomanno
- 8Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy,
| | - Yoshiyuki Ueno
- 9Division of Gastroenterology, Tohoku Graduate University School of Medicine, Sendai, Japan; and
| | - Eugenio Gaudio
- 10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome;
| | - Shannon Glaser
- Department of Medicine, Division of 1Gastroenterology and ,4Scott & White Digestive Disease Research Center, and ,5Central Texas Veterans Health Care System, Temple, Texas;
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Taveira A, Pereira F, Fernandes M, Sawamura R, Nogueira-Barbosa M, Paula F. Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease. Braz J Med Biol Res 2010; 43:1127-34. [DOI: 10.1590/s0100-879x2010007500118] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Accepted: 10/07/2010] [Indexed: 01/27/2023] Open
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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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10
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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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Petrie Aronin CE, Sadik KW, Lay AL, Rion DB, Tholpady SS, Ogle RC, Botchwey EA. Comparative effects of scaffold pore size, pore volume, and total void volume on cranial bone healing patterns using microsphere-based scaffolds. J Biomed Mater Res A 2009; 89:632-41. [PMID: 18442122 DOI: 10.1002/jbm.a.32015] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Bony craniofacial deficits resulting from injury, disease, or birth defects remain a considerable clinical challenge. In this study, microsphere-based scaffold fabrication methods were use to study the respective effects of scaffold pore size, open pore volume, and total void volume fraction on osseous tissue infiltration and bone regeneration in a critical size rat cranial defect. To compare the healing effects of these parameters, three different scaffolds types were fabricated: solid 100 microm spheres, solid 500 microm spheres, and hollow 500 microm spheres. These constructs were implanted into surgically created rat calvarial defects. By 90-days post op, results of micro computed tomography (CT) analysis showed that all scaffolds generated similar amounts of new bone which was significantly greater than untreated controls. Interestingly, the spatial distribution of new bone within the defect area varied by scaffold group. MicroCT and histological analysis demonstrated healing restricted to the dural side in the hollow 500 microm group, whereas the solid 500 microm group demonstrated healing along the dural side and within the center of the defect. Solid 100 microm groups demonstrated healing along the dural layer, periosteal layer, and within the center of the defect. These results suggest that pore size and closed void volume may both play important roles in scaffold degradation patterns and associated bone healing.
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13
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Olivier BJ, Schoenmaker T, Mebius RE, Everts V, Mulder CJ, van Nieuwkerk KMJ, de Vries TJ, van der Merwe SW. Increased osteoclast formation and activity by peripheral blood mononuclear cells in chronic liver disease patients with osteopenia. Hepatology 2008; 47:259-67. [PMID: 18022900 DOI: 10.1002/hep.21971] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
UNLABELLED Osteoporosis is a common complication of chronic liver disease, and the underlying mechanisms are not understood. We aimed to determine if osteoclasts develop from osteoclast precursors in peripheral blood mononuclear cells (PBMCs) of chronic liver disease patients with osteopenia compared with controls. PBMCs were isolated and fluorescence-activated cell sorting was performed to quantify the activated T lymphocyte population and receptor activator of nuclear factor kappabeta ligand (RANKL) expression. The activated T lymphocyte populations were comparable for all 3 groups, and RANKL was not detectable. The percentage of CD14+CD11b+ cells containing osteoclast precursors was comparable between the 3 groups. To assess the formation and functional activity of osteoclasts formed from circulating mononuclear cells, PBMCs were cultured (1) without addition of cytokines, (2) with macrophage colony-stimulating factor (M-CSF), (3) with M-CSF and osteoprotegerin, and (4) with M-CSF and RANKL. The number of tartrate-resistant acid phosphatase-positive multinucleated cells and bone resorption was assessed. PBMCs from chronic liver disease patients with osteopenia formed more osteoclast-like cells, which, when cultured in the presence of M-CSF and RANKL resorbed more bone than controls. The number of osteoclast-like cells and the amount of bone resorption correlated with lumbar bone densities. Addition of M-CSF increased numbers of osteoclast-like cells formed in healthy controls; however, this was not observed in either of the chronic liver disease groups. Plasma levels of M-CSF were elevated in both patient groups compared with healthy controls. CONCLUSION Circulating mononuclear cells from chronic liver disease patients with osteopenia have a higher capacity to become osteoclasts than healthy controls or chronic liver disease patients without osteopenia. This could partially be due to priming with higher levels of M-CSF in the circulation.
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Affiliation(s)
- Brenda J Olivier
- Hepatology Research Laboratory, Department of Immunology and Internal Medicine, University of Pretoria, South Africa
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Kalantari F, Miao D, Emadali A, Tzimas GN, Goltzman D, Vali H, Chevet E, Auguste P. Cellular and molecular mechanisms of abnormal calcification following ischemia-reperfusion injury in human liver transplantation. Mod Pathol 2007; 20:357-66. [PMID: 17334330 DOI: 10.1038/modpathol.3800747] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recent studies suggest a possible link between calcification and ischemia-reperfusion injury following liver transplantation. Histological staining, immunolabeling, and biochemical and electron microscopy analyses were applied to assess the possible mechanism(s) of calcification in liver tissue. Although light microscopy studies did not reveal the presence of large necrotic or apoptotic areas, electron microscopy showed the presence of membrane-bound vacuolar structures in hepatocytes, indicative of cell damage. Myofibroblasts were abundant in regions surrounding and within calcification. In these precalcified and calcified areas, myofibroblasts expressed bone-specific matrix proteins, such as osteopontin, type 1 collagen and bone sialoprotein. In addition, transforming growth factor beta (TGFbeta)-1 and BMP2, two growth factors implicated in osteoblast differentiation, and Runx2 and Msx2, two transcription factors targets of TGFbeta-1 and BMP2, were also expressed in these myofibroblasts. These data suggest that liver calcification following transplantation may be a consequence of precipitation of hydroxylapatite emanating from necrotic or apoptotic hepatocytes associated with proliferation of myofibroblasts expressing bone-specific matrix proteins.
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Affiliation(s)
- Fariba Kalantari
- Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
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Lee J, Kim JH, Kim K, Jin HM, Lee KB, Chung DJ, Kim N. Ribavirin enhances osteoclast formation through osteoblasts via up-regulation of TRANCE/RANKL. Mol Cell Biochem 2006; 296:17-24. [PMID: 16909305 DOI: 10.1007/s11010-006-9293-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2006] [Accepted: 07/24/2006] [Indexed: 02/06/2023]
Abstract
Hepatitis C combination therapy comprising ribavirin and interferon-alpha causes dramatic improvement with the sustained virological response; however, this treatment may result in the loss of bone mineral density. To investigate the effects of ribavirin on bone cells, we examined osteoblast differentiation as well as the formation of osteoclasts from their precursors. Ribavirin enhances osteoclast formation through osteoblasts by up-regulation of TRANCE/RANKL gene expression, whereas it has no significant effect on either osteoblast differentiation or on bone formation. Understanding ribavirin's underlying mechanism of action on bone cells will enable the improved management of bone loss in chronic hepatitis C patients.
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Affiliation(s)
- Junwon Lee
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Korea
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van der Merwe SW, Conradie MM, Bond R, Olivier BJ, Fritz E, Nieuwoudt M, Delport R, Slavik T, Engelbrecht G, Kahn D, Shephard EG, Kotze MJ, de Villiers NP, Hough S. Effect of rapamycin on hepatic osteodystrophy in rats with portasystemic shunting. World J Gastroenterol 2006; 12:4504-10. [PMID: 16874862 PMCID: PMC4125637 DOI: 10.3748/wjg.v12.i28.4504] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study if T-cell activation related to portasystemic shunting causes osteoclast-mediated bone loss through RANKL-dependent pathways. We also investigated if T-cell inhibition using rapamycin would protect against bone loss in rats.
METHODS: Portasystemic shunting was performed in male Sprague-Dawley rats and rapamycin 0.1 mg/kg was administered for 15 wk by gavage. Rats received powderized chow and supplemental feeds to prevent the effects of malnutrition on bone composition. Weight gain and growth was restored after surgery in shunted animals. At termination, biochemical parameters of bone turnover and quantitative bone histology were assessed. Markers of T-cell activation, inflammatory cytokine production, and RANKL-dependent pathways were measured. In addition, the roles of IGF-1 and hypogonadism were investigated.
RESULTS: Portasystemic shunting caused low turnover osteoporosis that was RANKL independent. Bone resorbing cytokine levels, including IL-1, IL-6 and TNFα, were not increased in serum and TNFα and RANKL expression were not upregulated in PBMC. Portasystemic shunting increased the circulating CD8+ T-cell population. Rapamycin decreased the circulating CD8+ T-cell population, increased CD8+ CD25+ T-regulatory cell population and improved all parameters of bone turnover.
CONCLUSION: Osteoporosis caused by portasystemic shunting may be partially ameliorated by rapamycin in the rat model of hepatic osteodystrophy.
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Affiliation(s)
- Schalk W van der Merwe
- Department of Internal Medicine and Gastroenterology, Hepatology and GI- Research laboratory, University of Pretoria, PO Box 1649, Faerie Glen, Pretoria 0043, South Africa.
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17
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Ferencz V, Horváth C, Kári B, Gaál J, Mészáros S, Wolf Z, Hegedus D, Horváth A, Folhoffer A, Szalay F. Bone disorders in experimentally induced liver disease in growing rats. World J Gastroenterol 2006; 11:7169-73. [PMID: 16437666 PMCID: PMC4725093 DOI: 10.3748/wjg.v11.i45.7169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the change of bone parameters in a new model of experimentally induced liver cirrhosis and hepatocellular carcinoma (HCC) in growing rats. METHODS Fischer-344 rats (n = 55) were used. Carbon tetrachloride (CCl(4)), phenobarbital (PB), and a single diethylnitrosamine (DEN) injection were used. Animals were killed at wk 8 and 16. Bone mineral content, femoral length, cortical index (quotient of cortical thickness and whole diameter) and ultimate bending load (F(max)) of the femora were determined. The results in animals treated with DEN+PB+CCl(4) (DPC, n = 21) were compared to those in untreated animals (UNT, n = 14) and in control group treated only with DEN+PB (DP, n = 20). RESULTS Fatty liver and cirrhosis developed in each DPC-treated rat at wk 8 and HCC was presented at wk 16. No skeletal changes were found in this group at wk 8, but each parameter was lower (P<0.05 for each) at wk 16 in comparison to the control group. Neither fatty liver nor cirrhosis was observed in DP-treated animals at any time point. Femoral length and F(max) values were higher (P<0.05 for both) in DP-treated animals at wk 8 compared to the UNT controls. However, no difference was found at wk 16. CONCLUSION Experimental liver cirrhosis and HCC are accompanied with inhibited skeletal growth, reduced bone mass, and decreased mechanical resistance in growing rats. Our results are in concordance with the data of other studies using different animal models. A novel finding is the transiently accelerated skeletal growth and bone strength after a 8-wk long phenobarbital treatment following diethylnitrosamine injection.
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Affiliation(s)
- Viktória Ferencz
- 1st Department of Internal Medicine, Semmelweis University, Koranyi S. 2/A, H-1083 Budapest, Hungary
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18
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Smith DLH, Shire NJ, Watts NB, Schmitter T, Szabo G, Zucker SD. Hyperbilirubinemia is not a major contributing factor to altered bone mineral density in patients with chronic liver disease. J Clin Densitom 2006; 9:105-13. [PMID: 16731439 DOI: 10.1016/j.jocd.2005.10.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2005] [Revised: 09/06/2005] [Accepted: 10/03/2005] [Indexed: 12/28/2022]
Abstract
Reduced bone density is commonly encountered in patients with chronic liver disease. Prior studies have shown that unconjugated bilirubin inhibits osteoblast activity and function in vitro and in animal models of bone mineralization. To determine whether hyperbilirubinemia promotes the development of hepatic osteodystrophy, bone mineral density (BMD) was measured by dual energy X-ray absorptiometry in a cohort of 86 consecutive patients with chronic liver disease referred for liver transplant evaluation. The mean age of the study population was 52 years (range, 22-73), in which 52% were female and 90% were white. Average bone density values were significantly lower than expected for age, race, and sex, with Z-scores for the femoral neck and spine of -0.50 (95% confidence interval [CI] -0.63 to -0.37; p=0.0003) and -0.69 (95% CI -0.85 to -0.52; p=0.0001), respectively. Sixty-one subjects (71%) exhibited reduced BMD (T-score of femoral neck or spine<or=-1 standard deviation [SD] below the young-adult mean), and 18 subjects (21%) met criteria for osteoporosis (T-score<-2.5 SD). Stepwise logistic regression analyses identified significant associations between BMD and serum creatinine, alkaline phosphatase, age, and gender. On the other hand, neither unconjugated, nor conjugated, nor total serum bilirubin levels were found to predict diminished BMD. The lack of association between serum unconjugated bilirubin levels and bone mineralization was validated in hyperbilirubinemic Gunn rats, in which BMD and serum osteocalcin levels were no different than in wild-type rodents. In conclusion, the finding that serum bilirubin levels do not correlate with reduced BMD in patients with end-stage liver disease, and that chronic unconjugated hyperbilirubinemia does not lead to alterations in bone mineralization in Gunn rats, suggests that bilirubin is not a major contributing factor to hepatic osteodystrophy.
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Affiliation(s)
- Darcey L H Smith
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45267-0595, USA
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19
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Abstract
This article discusses the clinical importance of hepatic osteopenia, the identification of risk factors for the individual patient, and the selection of patients, timing, and methods for diagnostic screening. General supportive measures to maximize bone health should be used in all patients at risk. In addition, for the patient with established osteoporosis, specific therapeutic measures may be justified, despite the lack of adequate randomized trials of these agents in patients with hepatic osteopenia.
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Affiliation(s)
- J Eileen Hay
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, Southwest, Rochester, MN 55905, USA.
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20
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Delport M, Maas S, van der Merwe SW, Laurens JB. Quantitation of hydroxyproline in bone by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 804:345-51. [PMID: 15081929 DOI: 10.1016/j.jchromb.2004.01.039] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2003] [Revised: 01/20/2004] [Accepted: 01/20/2004] [Indexed: 01/11/2023]
Abstract
A validated gas chromatography (GC)-mass spectrometric (MS) method for the analysis of hydroxyproline in rat femur is reported. Hydroxyproline in bone hydrolysates was extracted with an anion exchange resin and the N(O)-tert-butyldimethylsilyl derivatives analyzed by GC-MS. The hydroxyproline concentration was estimated relative to pipecolic acid, 3,4-dehydroproline and n-tetracosane as internal standards. The mass-to-charge ratios (m/z) for the ions used for quantitation by single ion monitoring were 314 m/z for hydroxyproline, 198 m/z for pipecolic acid, 256 m/z for dehydroproline and 57 m/z for n-tetracosane. A coefficient of variation of 5.8% was achieved and the limit of detection was calculated to be 0.233 micromol/l bone hydrolysate.
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Affiliation(s)
- M Delport
- Department of Chemical Pathology, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa
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