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Ley D, Saha S. Menopause and gastrointestinal health and disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-025-01075-7. [PMID: 40410564 DOI: 10.1038/s41575-025-01075-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/24/2025] [Indexed: 05/25/2025]
Abstract
Menopause has far-reaching effects on human physiology, including the gastrointestinal tract, and can negatively influence the quality of life of women who are affected. Menopause can have multiple effects on gastrointestinal function, including altering gut motility and changing the composition of the gut microbiota. As a result, some gastrointestinal and hepatic conditions are more common among individuals in peri- and postmenopause, and people with these conditions before menopause might also experience greater symptom severity and worse health-related quality of life during this time. The use of hormone replacement therapy to treat menopausal symptoms might also affect gastrointestinal health and well-being. Individuals in postmenopause are at risk for bone remodelling and osteoporosis due to ageing and loss of sex hormones. However, secondary osteoporosis can also occur due to medications used to treat gastrointestinal conditions (for example, glucocorticoids and other immunosuppressive medications) and the conditions themselves (for example, autoimmune disease or coeliac disease). Although all people who menstruate will eventually transition to menopause, there are relatively few studies evaluating the effect of menopause on gastrointestinal symptoms and quality of life. This Review aims to summarize available evidence and highlight areas where research is needed.
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Affiliation(s)
- Dana Ley
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sumona Saha
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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Jurado S, Parés A, Peris P, Combalia A, Monegal A, Guañabens N. Bilirubin increases viability and decreases osteoclast apoptosis contributing to osteoporosis in advanced liver diseases. Bone 2022; 162:116483. [PMID: 35787483 DOI: 10.1016/j.bone.2022.116483] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 12/19/2022]
Abstract
Bilirubin and bile acids have deleterious effects on osteoblasts, which may explain the low bone formation of liver diseases with cholestasis. Although there is some clinical evidence of increased bone resorption in this condition, the effects of these substances on osteoclasts are unknown. The objective was to analyze the effects of bilirubin and bile acids -lithocholic acid (LCA) and ursodeoxycholic acid (UDCA)- on osteoclast viability and apoptosis, and on the expression of osteoclast-related microRNAs (miRNAs). RAW 264.7 cells and human PBMCs were differentiated into osteoclasts. Success in differentiation was assessed by TRAP stain and osteoclast-specific gene expression; osteoclast activity was detected by the resorption pits in Corning® Osteo Assay Surface Plates. Cells were treated with camptothecin (CAM) or with bilirubin, LCA or UDCA, at several concentrations and combinations, including non-treated cells as control. Cell viability was measured using WST-1 assay and apoptosis assessing Caspase-3 by Western blot. Expression of miR-21a, miR-29b, miR-31, miR-148a, miR-155 and miR-223 were analyzed by Real Time. Viability increased gradually in osteoclasts differentiated from RAW 264.7 cells, as the concentration of bilirubin increased, being particularly high with bilirubin 100 μM (61 %) as compared to the untreated control (p < 0.007). Viability decreased significantly with CAM, LCA and UDCA (80 %, 62 % and 27 %, respectively), effects which were abolished by bilirubin. Moreover, bilirubin increased viability in osteoclasts derived from human PBMCs (p < 0.03). Caspase-3 decreased by 46 % with bilirubin 50 μM and increased 10-fold with LCA 100 μM and CAM (p < 0.01). Bilirubin increased miR-21 and miR-148a expression as compared to controls (115 % and 59 %, respectively; p < 0.007). In conclusion, bilirubin increases viability and decreases apoptosis of osteoclasts, and overexpresses the osteoclastogenic miR-21 and miR-148a. The effects of bilirubin counteract the actions of LCA and UDCA. Therefore, bilirubin may contribute to the increased bone resorption and to the development of osteoporosis in advanced liver diseases.
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Affiliation(s)
- Susana Jurado
- IDIBAPS-Hospital Clinic, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
| | - Albert Parés
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Pilar Peris
- Metabolic Bone Diseases Unit, Department of Rheumatology, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Andreu Combalia
- Orthopedics Department, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Ana Monegal
- Metabolic Bone Diseases Unit, Department of Rheumatology, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Núria Guañabens
- Metabolic Bone Diseases Unit, Department of Rheumatology, Hospital Clínic, University of Barcelona, Barcelona, Spain
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Pugliese N, Arcari I, Aghemo A, Lania AG, Lleo A, Mazziotti G. Osteosarcopenia in autoimmune cholestatic liver diseases: Causes, management, and challenges. World J Gastroenterol 2022; 28:1430-1443. [PMID: 35582674 PMCID: PMC9048470 DOI: 10.3748/wjg.v28.i14.1430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/05/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the most common cholestatic liver diseases (CLD) in adults and are both characterized by an immune pathogenesis. While primary biliary cholangitis is a model autoimmune disease, with over 90% of patients presenting very specific autoantibodies against mitochondrial antigens, PSC is considered an immune mediated disease. Osteoporosis is the most common bone disease in CLD, resulting in frequent fractures and leading to significant morbidity. Further, sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients. The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected. Although timely diagnosis, prevention, and management of osteosarcopenia are crucial to limit the consequences, there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD. International guidelines recommend screening for bone disease at the time of diagnosis of CLD. However, the optimal monitoring strategies and treatments have not been defined yet and vary among centers. We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD, and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.
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Affiliation(s)
- Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ivan Arcari
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Andrea G Lania
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Gherardo Mazziotti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
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Bukhari T, Jafri L, Majid H, Khan AHH, Siddiqui I. Determining Bone Turnover Status in Patients With Chronic Liver Disease. Cureus 2021; 13:e14479. [PMID: 33996337 PMCID: PMC8120131 DOI: 10.7759/cureus.14479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2020] [Indexed: 11/05/2022] Open
Abstract
Introduction Hepatic osteodystrophy is an osteoporotic bone disease that occurs in chronic liver disease patients. The global prevalence of osteoporosis in patients with chronic liver disease is 30% to 40%. The pathogenesis of hepatic bone disease is not clear, but it occurs due to unstable bone remodeling with increased bone resorption and decreases bone formation. There has been an interest in determining the clinical utility of bone turnover markers (BTMs) in the assessment of osteoporosis in chronic liver patients. Methods This was a cross-sectional study conducted in patients with chronic liver disease at the section of chemical pathology, department of pathology and laboratory medicine, Aga Khan University (AKU). A total of 50 patients with age >8 years and a history of liver disease >6 months were recruited from January to October 2019. Liver function tests, i.e. aspartate aminotransferase (AST), alanine transaminase (ALT), albumin, and bilirubin, along with clinical signs of liver disease chronicity, were noted. The samples for BTMs, i.e. total serum alkaline phosphatase (ALP) and serum C-terminal telopeptide of type-1 collagen (CTX) were withdrawn and analyzed on Microlab (ELItech Group, Puteaux, France) and ADVIA Centaur (Siemens Diagnostics, NY), respectively. Results The majority of patients were males (n=34, 68%). Twenty-four (48%) patients suffered from fibrosis while 26 (52%) were without fibrosis. Median platelet count (68×109/L (102.5-50)) and median cholesterol levels (102.5 mg/dl (147-99.5)) were decreased, whereas gamma-glutamyl transferase (GGT) levels were higher in the fibrosis group as compared to the non-fibrosis group. The median levels of total ALP were 91.5 IU/L (103-82), and the median levels of CTX were 0.24 pg/ml (0.34-0.21). Conclusion In the present study, no significant difference was found in the BTMs of patients with and without chronic liver disease (CLD). However, there was a positive and significant correlation of BTMs, particularly CTX with age, bilirubin levels, and hepatomegaly.
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Affiliation(s)
- Tayyaba Bukhari
- Pathology & Laboratory Medicine, Aga Khan University Hospital, Karachi, PAK
| | - Lena Jafri
- Pathology & Laboratory Medicine, Aga Khan University Hospital, Karachi, PAK
| | - Hafsa Majid
- Pathology & Laboratory Medicine, Aga Khan University Hospital, Karachi, PAK
| | - Aysha Habib H Khan
- Pathology & Laboratory Medicine, Aga Khan University Hospital, Karachi, PAK
| | - Imran Siddiqui
- Pathology & Laboratory Medicine, Aga Khan University Hospital, Karachi, PAK
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Parés A, Guañabens N. Primary biliary cholangitis and bone disease. Best Pract Res Clin Gastroenterol 2018; 34-35:63-70. [PMID: 30343712 DOI: 10.1016/j.bpg.2018.06.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 06/08/2018] [Indexed: 01/31/2023]
Abstract
Osteoporosis, characterized by compromised bone strength leading to fragility fractures, is a common event in patients with primary biliary cholangitis (PBC). Osteomalacia, defined by poor bone mineralization is very uncommon. The pathogenesis of osteoporosis is not well clarified, but it mainly results from low bone formation. Few reports have revealed increased bone resorption, particularly in end-stage disease. The prevalence of osteoporosis is about 35% in the most significant studies, and it depends on the diagnostic criteria and severity of liver damage. Osteoporosis is associated with age, postmenopausal status, duration of PBC and advanced histological stage. Bone densitometry is the common method for the diagnosis of osteoporosis and should be performed in all patients with PBC. Lateral X-rays of the dorsal and lumbar spine should also be carried out to disclose vertebral fractures. There is no specific treatment but bisphosphonates, especially alendronate and ibandronate, efficiently increases bone mass and prevents bone loss. Despite these positive effects on bone mass no clear results on decreasing the fracture rate have been demonstrated, probably because the low number of patients included in the trials. The potential value of new agents requires further evaluation.
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Affiliation(s)
- Albert Parés
- Liver Unit, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
| | - Núria Guañabens
- Department of Rheumatology, Metabolic Bone Diseases Unit, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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Liu Z, Han T, Werner H, Rosen CJ, Schaffler MB, Yakar S. Reduced Serum IGF-1 Associated With Hepatic Osteodystrophy Is a Main Determinant of Low Cortical but Not Trabecular Bone Mass. J Bone Miner Res 2018; 33:123-136. [PMID: 28902430 PMCID: PMC5771972 DOI: 10.1002/jbmr.3290] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 08/31/2017] [Accepted: 09/06/2017] [Indexed: 12/11/2022]
Abstract
Hepatic osteodystrophy is multifactorial in its pathogenesis. Numerous studies have shown that impairments of the hepatic growth hormone/insulin-like growth factor-1 axis (GH/IGF-1) are common in patients with non-alcoholic fatty liver disease, chronic viral hepatitis, liver cirrhosis, and chronic cholestatic liver disease. Moreover, these conditions are also associated with low bone mineral density (BMD) and greater fracture risk, particularly in cortical bone sites. Hence, we addressed whether disruptions in the GH/IGF-1 axis were causally related to the low bone mass in states of chronic liver disease using a mouse model of liver-specific GH-receptor (GHR) gene deletion (Li-GHRKO). These mice exhibit chronic hepatic steatosis, local inflammation, and reduced BMD. We then employed a crossing strategy to restore liver production of IGF-1 via hepatic IGF-1 transgene (HIT). The resultant Li-GHRKO-HIT mouse model allowed us to dissect the roles of liver-derived IGF-1 in the pathogenesis of osteodystrophy during liver disease. We found that hepatic IGF-1 restored cortical bone acquisition, microarchitecture, and mechanical properties during growth in Li-GHRKO-HIT mice, which was maintained during aging. However, trabecular bone volume was not restored in the Li-GHRKO-HIT mice. We found increased bone resorption indices in vivo as well as increased basal reactive oxygen species and increased mitochondrial stress in osteoblast cultures from Li-GHRKO and the Li-GHRKO-HIT compared with control mice. Changes in systemic markers such as inflammatory cytokines, osteoprotegerin, osteopontin, parathyroid hormone, osteocalcin, or carboxy-terminal collagen cross-links could not fully account for the diminished trabecular bone in the Li-GHRKO-HIT mice. Thus, the reduced serum IGF-1 associated with hepatic osteodystrophy is a main determinant of low cortical but not trabecular bone mass. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Zhongbo Liu
- David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology New York University College of Dentistry New York, NY 10010-4086
| | - Tianzhen Han
- David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology New York University College of Dentistry New York, NY 10010-4086
| | - Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | | | | | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology New York University College of Dentistry New York, NY 10010-4086
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Diagnosis and Management of Cirrhosis-Related Osteoporosis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1423462. [PMID: 27840821 PMCID: PMC5093239 DOI: 10.1155/2016/1423462] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 10/03/2016] [Indexed: 12/20/2022]
Abstract
Management of cirrhosis complications has greatly improved, increasing survival and quality of life of the patients. Despite that, some of these complications are still overlooked and scarcely treated, particularly those that are not related to the liver. This is the case of osteoporosis, the only cirrhosis complication that is not solved after liver transplantation, because bone loss often increases after immunosuppressant therapy. In this review, the definitions of bone conditions in cirrhotic patients are analyzed, focusing on the more common ones and on those that have the largest impact on this population. Risk factors, physiopathology, diagnosis, screening strategies, and treatment of osteoporosis in cirrhotic patients are discussed, presenting the more striking data on this issue. Therapies used for particular conditions, such as primary biliary cirrhosis and liver transplantation, are also presented.
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López-Larramona G, Lucendo AJ, Tenías JM. Association between nutritional screening via the Controlling Nutritional Status index and bone mineral density in chronic liver disease of various etiologies. Hepatol Res 2015; 45:618-28. [PMID: 25059921 DOI: 10.1111/hepr.12395] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Revised: 07/04/2014] [Accepted: 07/21/2014] [Indexed: 12/13/2022]
Abstract
AIM Bone density disorders are prevalent in patients with chronic liver disease (CLD), who commonly present with hepatic osteodystrophy. However, the relationship between nutritional status and bone mineral density (BMD) has been scarcely studied in CLD. METHODS This single-center, cross-sectional study included outpatients consecutively diagnosed with CLD during a 1.5-year period. The nutritional status was assessed with the Controlling Nutritional Status (CONUT) index; dual-energy X-ray absorptiometry scans and parameters of bone mineral metabolism were carried out. Bone fracture risk was estimated with the World Health Organization FRAX tool. RESULTS Among the 126 patients recruited (58.7% male), osteopenia and osteoporosis were present in 31.1% and 10.7%, respectively. The 10-year fracture risk was significantly higher among women. Malnutrition estimated with the CONUT index was present in 29.9% of patients and was significantly more frequent in cirrhotic patients, 63.4% of whom were malnourished. Malnutrition stage directly correlated with hepatic function as expressed by the Model for End-Stage Liver Disease index. A non-significant relationship between CONUT-assessed nutritional status and BMD was documented. 25-Hydroxyvitamin-D3 (25[OH]-D3) and fracture risk correlated positively with the CONUT stage, and total cholesterol had an inverse relationship with BMD. CONCLUSION Malnutrition assessed by the CONUT was very frequent in patients with liver cirrhosis. The CONUT score inversely correlated with liver function, while malnutrition stage directly correlated with BMD, fracture risk and 25(OH)-D3. Total cholesterol showed a negative association with BMD in this population.
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Affiliation(s)
| | - Alfredo J Lucendo
- Gastroenterology Department, Hospital General de Tomelloso, Tomelloso, Spain
| | - José María Tenías
- Research Support Unit, Hospital Mancha-Centro, Alcázar de San Juan, Spain
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Shirazi M, Ameri A, Shafaroodi H, Motahhary P, Saleh T, Ghasemi M, Dehpour AR. Orthodontic tooth movement in cholestatic and cirrhotic rats. J Orthod 2014; 35:119-25; discussion 110-1. [DOI: 10.1179/146531207225022536] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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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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The role of serum cytokines in the pathogenesis of hepatic osteodystrophy in male cirrhotic patients. Gastroenterol Res Pract 2012; 2012:425079. [PMID: 23097664 PMCID: PMC3477708 DOI: 10.1155/2012/425079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Revised: 09/10/2012] [Accepted: 09/10/2012] [Indexed: 11/17/2022] Open
Abstract
Objective. In this study, we aimed to investigate the possible role of serum cytokines in the development of hepatic osteodystrophy. Matherial and Methods. 44 consecutive male cirrhotic patients (17 alcoholic, 20 hepatitis B, 7 hepatitis C), 15 age- and sex-matched chronic alcoholics without liver disease, and 17 age- and sex-matched healthy controls were included in the study during one year period. Bone mineral density was measured by dual X-ray absorptiometry in the lumbar vertebrate and femoral neck. Serum interleukin levels were measured by ELISA method. Results. Although osteopenia frequency between our cirrhotic patients was 20%, there was no difference in T-scores among the controls and other groups. Serum interleukin-1, interleukin-8, and tumor necrosis factor-alpha levels were not different between all groups. Serum interleukin-2 and interleukin-6 levels were higher in the cirrhotics than controls (P < 0.001). However, there were no significant difference between osteopenic and nonosteopenic cirrhotics. Conclusion. According to the results of the study in this small population of 44 male cirrhotic patients, frequency of hepatic osteopenia is small and serum interleukins 1, 2, 6, 8, and tumor necrosis factor-alpha may not play a role in the pathogenesis of hepatic osteodystrophy. Further studies in which large number of patients involved are necessary in this field.
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Moon SS, Lee YS, Kim SW. Association of nonalcoholic fatty liver disease with low bone mass in postmenopausal women. Endocrine 2012; 42:423-9. [PMID: 22407492 DOI: 10.1007/s12020-012-9639-6] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 02/16/2012] [Indexed: 12/13/2022]
Abstract
Osteoporosis is a disease associated with insulin resistant states such as central obesity, diabetes, and metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is also increased in such conditions. However, little is known about whether osteoporosis and nonalcoholic fatty liver disease are etiologically related to each other or not. We examined whether bone mineral density (BMD) is associated with NAFLD in pre- and postmenopausal women. Four hundred eighty-one female subjects (216 premenopausal and 265 postmenopausal) were enrolled. Lumbar BMD was measured using dual-energy X-ray absorptiometry. Liver ultrasonography was done to check the severity of fatty liver. We excluded subjects with a secondary cause of liver disease. Blood pressure, lipid profile, fasting plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase, and body mass index were measured in every subject. Mean lumbar BMD was lower in subjects with NAFLD than those without NAFLD in postmenopausal women (0.98 ± 0.01 vs. 1.01 ± 0.02 g/cm², P = 0.046). Multiple correlation analysis revealed a significant association between mean lumbar BMD and NAFLD in postmenopausal subjects after adjusting for age, body mass index, ALT, smoking status, and alcohol consumption (β coefficient -0.066, 95% CI -0.105 to -0.027, P = 0.001). Even after adjusting the presence of metabolic syndrome, the significance was maintained (β coefficient -0.043, 95% CI -0.082 to -0.004, P = 0.031). Lumbar BMD is related with NAFLD in postmenopausal females. We suggest that postmenopausal women with NAFLD may have a higher risk of osteoporosis than those without.
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Affiliation(s)
- Seong-Su Moon
- Department of Internal Medicine, Dongguk University School of Medicine, Dongdae-ro 87, Gyeongju, Gyeongbuk province 780-350, South Korea.
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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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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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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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16
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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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17
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Abstract
Osteoporosis, characterized by loss of bone strength leading to fragility fractures, is a common event in patients who have primary biliary cirrhosis. Although its pathogenesis is not well known, it results mainly from low bone formation. There is no specific treatment, but bisphosphonates, especially alendronate, effectively increases bone mass and prevents bone loss. Despite these favorable effects on bone mass, no clear effects on decreasing the fracture rate are demonstrated, probably because of the low number of patients included in the trials. The potential usefulness of new agents requires further evaluation.
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18
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Mounach A, Ouzzif Z, Wariaghli G, Achemlal L, Benbaghdadi I, Aouragh A, Bezza A, El Maghraoui A. Primary biliary cirrhosis and osteoporosis: a case-control study. J Bone Miner Metab 2008; 26:379-84. [PMID: 18600405 DOI: 10.1007/s00774-007-0833-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2007] [Accepted: 12/02/2007] [Indexed: 02/06/2023]
Abstract
Osteoporosis is a common complication of chronic liver disease, from cholestatic disorders to autoimmune, alcoholic, and posthepatitic cirrhosis. Osteoporosis appears more striking in patients with primary biliary cirrhosis (PBC) because the disease usually affects elderly women, who are naturally prone to osteoporosis. Our aims were (1) to compare the prevalence of osteoporosis (T-score <-2.5 SD) between PBC patients and a group of age-and sex-matched controls consisting of healthy subjects from the general population; and (2) to identify the main risk factors for the development of bone loss. Thirty-three women with PBC (mean age, 47.3 +/- 10.4 years) and 66 healthy subjects were enrolled in the study. Bone mineral density (BMD) was assessed at the lumbar spine by dual-photon X-ray absorptiometry. Bone metabolism was evaluated by measuring serum calcium corrected for serum albumin, 25-hydroxyvitamin D (25-OH vit D), parathyroid hormone, and osteocalcin. Vertebral fractures were analyzed using vertebral fracture assessment (VFA). The mean T-score was lower in the PBC group compared to healthy controls, with a significant statistical difference (-2.39 +/- 0.93 and -1.47 +/- 0.99 in lumbar spine and total hip, respectively, in the PBC group versus -0.99 +/- 0.51 and -0.56 +/- 1.14 in healthy controls (P < 0.001). The prevalence of osteoporosis was 51.5% in the PBC group versus 22.7% in healthy controls with a statistically significant difference (P = 0.004). BMD of the PBC group was significantly correlated positively with body mass index (BMI) and 25-OH vit D, and negatively with menopausal status, duration of disease, and parathyroid hormone (PTH) levels. Vertebral fractures were present in 9% of the patients. We found that osteoporosis is more prevalent in women with PBC than in the general population. BMI, menopausal status, duration of the disease, and vitamin D deficiency are the main risk factors for osteoporosis in this liver disease.
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Affiliation(s)
- Aziza Mounach
- Rheumatology and Physical Rehabilitation Department, Military Hospital Mohammed V, PO Box: 1018, Rabat, Morocco.
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Allocca M, Crosignani A, Gritti A, Benetti A, Zuin M, Podda M, Battezzati PM. Inadequate dietary intake but not renal tubular acidosis is associated with bone demineralization in primary biliary cirrhosis. Aliment Pharmacol Ther 2007; 25:219-27. [PMID: 17229245 DOI: 10.1111/j.1365-2036.2006.03181.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Metabolic bone disease associated with primary biliary cirrhosis (PBC) is inadequately characterized. Renal tubular acidosis (RTA) may lead to bone loss through chronic mobilization of skeletal calcium salts to buffer increased acid load. AIM To evaluate the prevalence of RTA in PBC and establish the relationships among bone mineral density (BMD), renal function and nutritional status. METHODS We enrolled 69 female patients with compensated PBC and 35 control patients with chronic hepatitis C. RTA was searched in all patients, and 24-h dietary recalls were collected at enrolment. BMD was measured by dual-energy X-ray absorptiometry at the femur neck, lumbar spine and radius ultradistalis sites. RESULTS No patients received a diagnosis of RTA. BMD values (Z-scores) showed only little deviation from normal population with no difference between PBC and controls. Osteopoenic PBC patients (T-score < 1) showed significantly lower daily phosphorus intake [median: 672 (288-1374) vs. 921 (253-1923) mg/day; P = 0.037], with a trend towards lower caloric intake than their nonosteopoenic counterparts. CONCLUSIONS Renal tubular acidosis is uncommon in compensated PBC. Cholestasis is not associated with an increased risk of bone demineralization. Inadequate dietary intake may be a preventable factor contributing to bone loss in PBC.
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Affiliation(s)
- M Allocca
- Division of Internal Medicine and Liver Unit, Department of Medicine, Surgery and Dentistry, School of Medicine San Paolo, University of Milan, Milan, Italy.
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20
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Affiliation(s)
- Albert Parés
- Liver Unit, Digestive Diseases Institute and Metabolic Bone Diseases Unit, Department of Rheumatology Hospital Clínic, IDIBAPS, Barcelona, Spain.
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21
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Boone RH, Cheung AM, Girlan LM, Heathcote EJ. Osteoporosis in primary biliary cirrhosis: a randomized trial of the efficacy and feasibility of estrogen/progestin. Dig Dis Sci 2006; 51:1103-12. [PMID: 16865577 DOI: 10.1007/s10620-006-8015-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2005] [Accepted: 04/27/2005] [Indexed: 01/27/2023]
Abstract
The optimal therapy for the prevention and treatment of osteoporosis in primary biliary cirrhosis (PBC) is unknown. Hormone replacement therapy (HRT) prevents osteoporosis, but may promote cholestasis. We performed a double-blind, randomized, placebo-controlled trial of transdermal estrogen/progestin in postmenopausal women with PBC. The 24-month study enrolled 31 patients, but trial uptake was limited and treatment arm dropout was significant. Placebo-treated patients had a higher percentage loss in femoral neck bone mineral density than actively treated patients (-3.76 +/- 1.37% versus 0.21 +/- 1.01%, respectively, P = .058). New fractures occurred in 2 patients on placebo, and in no patients on treatment. The mean monthly increase in bilirubin was not significantly different between groups, but individual data suggest HRT may worsen cholestasis. In conclusion, women with PBC have strong feelings about HRT, and recruitment for this intervention is difficult. Transdermal estrogen/progestin likely provides protection against bone loss in PBC patients, but may worsen cholestasis.
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Affiliation(s)
- Robert H Boone
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Pusl T, Beuers U. Extrahepatic manifestations of cholestatic liver diseases: pathogenesis and therapy. Clin Rev Allergy Immunol 2006. [PMID: 15879620 DOI: 10.1385/criai:] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pruritus, fatigue, and metabolic bone disease are frequent complications of cholestatic liver diseases, which can be quite distressing for the patient and can considerably reduce the quality of life. The molecular pathogenesis of these extrahepatic manifestations of cholestasis is poorly understood, and hypotheses to explain these symptoms are being discussed. This article provides treatment recommendations for the complications of cholestasis based on putative pathomechanisms and summarizes recent experimental and clinical data involving management options.
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Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
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23
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Pusl T, Beuers U. Extrahepatic manifestations of cholestatic liver diseases: pathogenesis and therapy. Clin Rev Allergy Immunol 2006; 28:147-57. [PMID: 15879620 DOI: 10.1385/criai:28:2:147] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pruritus, fatigue, and metabolic bone disease are frequent complications of cholestatic liver diseases, which can be quite distressing for the patient and can considerably reduce the quality of life. The molecular pathogenesis of these extrahepatic manifestations of cholestasis is poorly understood, and hypotheses to explain these symptoms are being discussed. This article provides treatment recommendations for the complications of cholestasis based on putative pathomechanisms and summarizes recent experimental and clinical data involving management options.
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Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
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24
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Kanda T, Yokosuka O, Hirasawa Y, Imazeki F, Nagao K, Saisho H. Occurrence of autoimmune hepatitis during the course of primary biliary cirrhosis: report of two cases. Dig Dis Sci 2006; 51:45-46. [PMID: 16416210 DOI: 10.1007/s10620-006-3083-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2003] [Accepted: 07/21/2003] [Indexed: 12/13/2022]
Affiliation(s)
- Tatsuo Kanda
- First Department of Medicine, Chiba University School of Medicine, Chiba, Japan.
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25
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Guañabens N, Parés A, Ros I, Caballería L, Pons F, Vidal S, Monegal A, Peris P, Rodés J. Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis. J Hepatol 2005; 42:573-7. [PMID: 15763344 DOI: 10.1016/j.jhep.2004.11.035] [Citation(s) in RCA: 124] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2004] [Revised: 11/12/2004] [Accepted: 11/26/2004] [Indexed: 12/22/2022]
Abstract
BACKGROUND Since primary biliary cirrhosis (PBC) is usually diagnosed in postmenopausal women with minor cholestasis, it has been questioned whether PBC itself represents a further risk for osteoporosis. AIM To assess the prevalence and risk factors for osteoporosis in an unselected series of women with PBC. PATIENTS AND METHODS 142 women with PBC (age: 54.3+/-0.8 years) and an age-matched control group. Osteoporosis was established by densitometry (bone mineral density below -2.5 T-score). Age, duration and severity of PBC, body mass index, menopausal status, histological stage and markers of bone turnover were assessed. RESULTS Prevalence of osteoporosis was higher in PBC (32.4%) than in normal women (11. 1%) (RR: 3.83, 95%CI: 2.59-5.67, P<0.001). Osteoporosis was associated with older age, menopausal status, body mass index, longer PBC duration, advanced histological stage, high bilirubin and alkaline phosphatase, and low albumin and prothrombin index. Regression analysis identified older age, higher Mayo risk score, lower body mass index and advanced histological stage but not menopause as the independent risk factors for osteoporosis. CONCLUSIONS Osteoporosis is more prevalent in women with PBC than in the general population. Age and severity of the disease, but not menopausal status, are the main risk factors for osteoporosis in this liver disease.
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Affiliation(s)
- Núria Guañabens
- Metabolic Bone Diseases Unit, Service of Rheumatology, Hospital Clínic, IDIBAPS, University of Barcelona, C/Villarroel 170, 08036-Barcelona, Spain.
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26
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Schiefke I, Fach A, Wiedmann M, Aretin AV, Schenker E, Borte G, Wiese M, Moessner J. Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection. World J Gastroenterol 2005; 11:1843-7. [PMID: 15793878 PMCID: PMC4305888 DOI: 10.3748/wjg.v11.i12.1843] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [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: Previous studies suggest that loss of bone mineral density (BMD) frequently occurs in patients with chronic viral liver disease, presenting with histologically proven liver cirrhosis. However, little is known about the occurrence of bone disease in non-cirrhotic patients with chronic hepatitis B or C. Therefore, it was the aim of this study to evaluate this particular population for BMD and bone turnover markers.
METHODS: Biochemical markers of bone turnover and BMD were measured in 43 consecutive patients with HCV (n = 30) or HBV (n = 13) infection without histological evidence for liver cirrhosis. Mean age was 49 years (range 26-77 years). BMD was measured by dual X-ray absorptiometry in the femoral neck (FN) and the lumbar spine (LS) region. In addition, bone metabolism markers were measured.
RESULTS: BMD was lowered in 25 (58%) of the patients with chronic hepatitis B or C (FN: 0.76 (0.53-0.99); LS: 0.96 (0.62-1.23) g/cm2). Eight (32%) osteopenic patients were diagnosed with osteoporosis. Bone-specific alkaline phosphatase (P = 0.005) and intact parathyroid hormone (iPTH) (P = 0.001) were significantly elevated in the more advanced stages of fibrosis. Mean T-score value was lower in patients with chronic hepatitis C as compared to patients suffering from chronic hepatitis B; however, the difference was not statistically significant (P = 0.09).
CONCLUSION: There was a significantly reduced BMD in non-cirrhotic patients with chronic hepatitis B or C infection. Alterations of bone metabolism already occurred in advanced liver fibrosis without cirrhosis. According to our results, these secondary effects of chronic viral hepatitis should be further investigated.
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Affiliation(s)
- Ingolf Schiefke
- Department of Medicine II, University of Leipzig, Philipp-Rosenthal Str. 27, 04103 Leipzig, Germany.
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27
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Guichelaar MMJ, Malinchoc M, Sibonga JD, Clarke BL, Hay JE. Bone histomorphometric changes after liver transplantation for chronic cholestatic liver disease. J Bone Miner Res 2003; 18:2190-9. [PMID: 14672354 DOI: 10.1359/jbmr.2003.18.12.2190] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
UNLABELLED Thirty-three patients with cholestatic liver disease underwent histomorphometric assessment of paired bone biopsy specimens at time of orthotopic liver transplantation (OLT) and 4 months thereafter. At 4 months after OLT, bone metabolism improved, with bone formation increasing to normal and no change in bone resorption. Early post-transplant bone loss may be attributed to an additional insult to bone formation early after transplantation. INTRODUCTION Patients with advanced liver disease, especially chronic cholestasis, often have osteopenia, which worsens early after orthotopic liver transplantation (OLT) before starting to recover. The changes in bone metabolism leading to this rapid loss of bone after OLT, and to its recovery, are poorly defined. MATERIALS AND METHODS In thirty-three patients with advanced chronic cholestatic liver disease, tetracycline-labeled bone biopsy specimens were analyzed prospectively at time of OLT and at 4 months after OLT, as part of a randomized trial to study the efficacy of calcitonin on post-transplant bone loss. Hierarchical cluster analysis of histomorphometric parameters was performed in an attempt to establish the functional grouping of individual histomorphometric parameters before and after OLT. RESULTS AND CONCLUSIONS Results showed that from the time of OLT to 4 months after OLT, bone mineral density of the lumbar spine and histomorphometric parameters of bone volume decreased, consistent with early post-transplant bone loss. Histomorphometric resorption parameters were increased before OLT, with no change after OLT. Histomorphometric formation parameters increased from low values before OLT to normal values at 4 months after OLT, with the exception of mean wall thickness values, which further decreased after OLT, suggesting an additional insult to bone formation during the study period. Histomorphometric changes after OLT were similar in female and male patients, pre- and postmenopausal women, and in patients treated and not treated with calcitonin. Hierarchical cluster analysis suggested that before OLT, bone resorption was functioning independently of bone formation, but that by 4 months after OLT, their coupled relationship had improved. Therefore, despite post-transplant bone loss, by 4 months after OLT, bone metabolism had improved, with increased bone formation and more coupled bone balance, as suggested by hierarchical cluster analysis.
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Affiliation(s)
- Maureen M J Guichelaar
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
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Crawford BAL, Kam C, Donaghy AJ, McCaughan GW. The heterogeneity of bone disease in cirrhosis: a multivariate analysis. Osteoporos Int 2003; 14:987-94. [PMID: 14504696 DOI: 10.1007/s00198-003-1495-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2002] [Accepted: 05/15/2003] [Indexed: 02/07/2023]
Abstract
This study aimed to assess the clinical, biochemical and hormonal factors contributing to low bone density in a large ambulatory group of patients with cirrhosis of diverse aetiology. Bone density of the lumbar spine, neck of femur, total hip, total body, as well as total body fat, was measured by dual X-ray (DEXA) absorptiometry in 81 men and 32 women (average age 50.3 years). Morning blood and urine samples were taken for hormonal and biochemical analysis. Viral hepatitis was the most common cause of cirrhosis (54%) and the severity of cirrhosis ranged from Child-Pugh A5-C14. Osteoporosis was most common in the lumbar spine but was present at any site in 31% of women and 22% of men, with osteopenia present in another 40% of both genders. Urinary deoxypyridinoline, a marker of bone resorption, was elevated in 56% of patients and was associated with increasing severity of cirrhosis and a higher prevalence of osteoporosis, particularly of the lumbar spine. Hip-bone density was primarily affected by low 25-hydroxyvitamin D levels and was associated with secondary hyperparathyroidism in one third of these patients. Additional important predictors for low bone density at all sites were age in women and testosterone in men. These findings indicate that, although the pathophysiology of osteoporosis in chronic liver disease is heterogeneous, high bone turnover may be the underlying pathophysiological mechanism in a significant subgroup of cirrhotic patients and may reflect metabolic effects of hypogonadism or secondary hyperparathyroidism on bone.
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Affiliation(s)
- Bronwyn A L Crawford
- Department of Endocrinology, Royal Prince Alfred Hospital and University of Sydney, Camperdown, NSW 2050, Australia.
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29
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Affiliation(s)
- J Eileen Hay
- Mayo Clinic, 200 First street SW, Rochester, MN 55905, USA.
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30
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Abstract
Osteoporosis remains a serious potential complication of liver transplantation, although its incidence may be significantly reduced by the use of lower doses of glucocorticoids. Additional factors likely to contribute to its pathogenesis include other immunosuppressive agents, particularly cyclosporin A and FK506, vitamin D insufficiency, secondary hyperparathyroidism, hypogonadism and pre-existing bone disease. Bone density assessment and spinal X-rays should be performed before transplantation to assess subsequent fracture risk and vitamin D and gonadal status assessed. Measures should be taken to optimise bone health prior to transplantation; in those with low bone mineral density and/or previous fragility fracture, prophylaxis against bone loss after transplantation should be considered. Although anti-fracture efficacy has not been established for any agent there is evidence, mainly in patients undergoing other forms of solid organ transplantation, that repeated infusions of pamidronate may be effective in preventing bone loss.
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Affiliation(s)
- Juliet E Compston
- Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom.
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31
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Guichelaar MMJ, Malinchoc M, Sibonga J, Clarke BL, Hay JE. Bone metabolism in advanced cholestatic liver disease: analysis by bone histomorphometry. Hepatology 2002; 36:895-903. [PMID: 12297836 DOI: 10.1053/jhep.2002.36357] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite the clinical importance of cholestatic osteopenia, little is known about its pathophysiologic mechanism. By tetracycline-labeled histomorphometric analysis of bone biopsies taken at the time of liver transplantation, we prospectively evaluated bone resorption and formation in 50 consecutive patients with advanced primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Histomorphometric analysis confirmed low bone volume parameters, consistent with the mean T-score of the lumbar spine of -1.9 by dual energy x-ray absorptiometry. Dynamic (bone formation rates, adjusted apposition rates) and static (osteoid markers, osteoblast number) parameters of bone formation were decreased in cholestatic patients with no abnormalities in mineralization. Increased osteoclast numbers and increased eroded surface areas suggested increased bone resorption, and this was supported in female patients by increased trabecular separation and decreased trabecular number. Male cholestatic patients, however, did not have significant increases in resorption parameters, although they were as osteopenic as female patients and had low bone formation markers. Bone histomorphometric changes were similar in PBC and PSC, suggesting an etiologic effect of chronic cholestasis rather than the individual diseases. Cancellous bone volume and osteoid markers correlated with bone mineral density measurements but no correlations were found between histomorphometric parameters and biochemical markers of bone metabolism. In conclusion, cholestatic osteopenia appears to result from a combination of decreased bone formation and increased resorption, especially in female patients, but the relative importance of these two abnormalities and their actual etiology remain to be elucidated.
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Abstract
Pruritus, fatigue and metabolic bone disease represent three major extrahepatic manifestations of chronic cholestatic liver disease that considerably affect the patient's quality of life. The present article reviews pathogenetic aspects of and current therapeutic approaches to extrahepatic manifestations of cholestatic liver disease. Pathogenesis of pruritus of cholestasis remains poorly understood. The involvement of putative peripherally acting pruritogens, such as bile acids or endogenous opioids, is being discussed. More recently, central mechanisms, including an increased central opioidergic tone and pertubations in the serotonergic system have been proposed. Treatment of the underlying disease is beneficial also for the control of cholestasis-associated pruritus. Current therapeutic recommendations include ursodeoxycholic acid, cholestyramine, rifampicin and opioid antagonists. Liver transplantation may be indicated when severe pruritus is refractory to medical treatment. Fatigue is being recognized as the most frequent and one of the most disabling complaints in chronic cholestasis. Fatigue is presumably of central origin and its association with other neuropsychiatric disorders (e.g. depression, obsessive-compulsive disorders) is consistent with defective central neurotransmission. No specific therapies are currently available and a healthy lifestyle, regular sleep and avoidance of unnecessary stress and other precipiting factors are recommended. Antidepressant therapy may be warranted in selected patients. Osteopenia and osteoporosis are common in chronic cholestatic liver disease, whereas osteomalacia is rare. The pathophysiology of cholestasis-associated metabolic bone disease is regarded as multifactorial. Therapeutic recommendations include regular exercise, calcium and vitamin D supplementation in late stage disease, hormone replacement therapy in postmenopausal women and bisphosphonates.
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Affiliation(s)
- Helena Glasova
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
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33
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Ackerman Z, Weinreb M, Amir G, Pollak RD. Bone mineral metabolism and histomorphometry in rats with cholestatic liver disease. LIVER 2002; 22:166-72. [PMID: 12028412 DOI: 10.1046/j.0106-9543.2002.01566.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The etiology of osteopenia in cholestatic liver disease is uncertain. An animal model is needed in order to study the efficacy of therapeutic agents. AIMS In order to characterise the bone disease in rats with cholestatic liver disease. METHODS Four-month old male Sprague-Dawley bile duct-ligated (BDL) and sham-operated (SO) rats were studied. Twenty-eight days after surgery serum osteocalcin, a bone-formation marker, urinary deoxypyridinoline (DPD) cross-links, a resorption marker, and 25-hydroxyvitamin D3 were determined. Static and dynamic (tetracycline-based) histomorphometric analysis was performed on femurs and tibiae. RESULTS All BDL rats developed biliary cirrhosis. Bile duct-ligated rats had lower bone mass, reflected in statistically significantly 13.5% lower femoral dry-weight, 16% lower femoral ash-weight, 42.7% lower tibial cancellous bone area and 19% lower trabecular thickness, compared with SO rats. Bile duct-ligated rats exhibited decreased bone formation manifested by statistically significantly 70% lower tetracycline double-labelling, 40% lower mineralising surface, 51% lower bone-formation rate and 47% lower osteocalcin compared with SO rats. Deoxypyridinoline levels were 20% lower in BDL rats. Bile duct-ligated rats had 52% lower serum 25-hydroxyvitamin D3 level, but no significant increase in cortical osteoid area. CONCLUSIONS Bile duct-ligated rats develop osteopenia characterised by low bone-formation rate, and can be used for studying therapeutic agents for patients with cholestatic liver disease displaying similar bone changes.
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Affiliation(s)
- Zvi Ackerman
- Department of Medicine, Hadassah University Hospital, Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
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Menon KV, Angulo P, Weston S, Dickson ER, Lindor KD. Bone disease in primary biliary cirrhosis: independent indicators and rate of progression. J Hepatol 2001; 35:316-23. [PMID: 11592591 DOI: 10.1016/s0168-8278(01)00144-1] [Citation(s) in RCA: 130] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS To identify indicators of osteoporosis and to determine the rate of bone loss in patients with primary biliary cirrhosis (PBC). METHODS Bone mineral density of the lumbar spine and hip was measured at annual intervals over 7 years of follow-up in 176 patients with PBC. RESULTS Osteoporosis (t-score below -2.5) was found in 20% of patients and occurred 32.1 times more frequently in patients with PBC than expected. Patients with histologic stage 3 or 4 disease had a 5.4-fold increased risk of osteoporosis compared to patients with stage 1 or 2. Age, body mass index, advanced stage (3 or 4), and history of fractures were the only independent indicators of osteoporosis. After 3 years of follow up, the rate of bone loss in patients with stage 1 or 2 increased and equaled that seen in patients with stage 3 or 4. Serum bilirubin level was the only variable independently associated with the rate of bone loss over time. CONCLUSIONS Severity of the liver disease contributes significantly to the severity of bone disease in PBC. PBC patients who are older, thinner and have more advanced liver disease may have the most benefit from bone density measurements and treatment for their osteoporosis.
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Affiliation(s)
- K V Menon
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, USA
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35
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Hay JE, Malinchoc M, Dickson ER. A controlled trial of calcitonin therapy for the prevention of post-liver transplantation atraumatic fractures in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 2001; 34:292-8. [PMID: 11281559 DOI: 10.1016/s0168-8278(00)00093-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Accelerated bone loss occurs early after liver transplantation (OLT) and, in cholestatic patients with pre-existing osteopenia, causes spontaneous fracturing. This study aimed to investigate the efficacy of calcitonin, a powerful inhibitor of bone resorption, in preventing or reducing the accelerated rate of bone loss and fracturing which occurs in patients with primary biliary cirrhosis and primary sclerosing cholangitis early after OLT. METHODS Sixty-three patients undergoing OLT for primary biliary cirrhosis (n = 26) and primary sclerosing cholarigitis (n = 37) were randomized to receive: (a), 100 IU/day of salmon calcitonin subcutaneously for the first 6 months posttransplant; or (b), no therapy. At pretransplant, and at 4 and 12 months after OLT, patients were investigated clinically, biochemically, by bone mineral density of the lumbar spine, and by radiographs of the thoracolumbar spine, chest and site of any bone pain. RESULTS The bone mineral density of the lumbar spine fell equally at 4 months in both groups, from 0.85 to 0.81 g/cm2 in calcitonin-treated patients (n = 29) and from 0.88 to 0.82 g/cm2 in controls (n = 34); at 12 months, both groups had stabilized to 0.83 g/cm2. Fracturing was the same in both groups. CONCLUSIONS Calcitonin therapy for the first 6 months after OLT is unable to prevent or reduce accelerated bone loss or spontaneous fractures which occur in the first posttransplant year.
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MESH Headings
- Adult
- Bone Density/drug effects
- Bone Diseases, Metabolic/etiology
- Bone Diseases, Metabolic/metabolism
- Bone Diseases, Metabolic/prevention & control
- Bone Resorption/etiology
- Bone Resorption/metabolism
- Bone Resorption/prevention & control
- Calcitonin/therapeutic use
- Cholangitis, Sclerosing/complications
- Cholangitis, Sclerosing/metabolism
- Cholangitis, Sclerosing/surgery
- Female
- Fractures, Spontaneous/etiology
- Fractures, Spontaneous/prevention & control
- Humans
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/surgery
- Liver Transplantation/adverse effects
- Liver Transplantation/physiology
- Male
- Middle Aged
- Time Factors
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Affiliation(s)
- J E Hay
- Division of Gastroenterology, Mayo Medical Center, Rochester, MN 55905, USA.
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36
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Springer JE, Cole DE, Rubin LA, Cauch-Dudek K, Harewood L, Evrovski J, Peltekova VD, Heathcote EJ. Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis. Gastroenterology 2000; 118:145-51. [PMID: 10611163 DOI: 10.1016/s0016-5085(00)70423-9] [Citation(s) in RCA: 100] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Hepatic osteodystrophy is a complication of primary biliary cirrhosis (PBC). Allelic polymorphisms of the vitamin D receptor (VDR) gene are related to bone mineral density (BMD) in normal cohorts and those with primary osteoporosis. We sought to establish the prevalence of reduced bone mass in PBC, correlate BMD with VDR gene polymorphisms, and identify risk factors for the development of hepatic osteodystrophy. METHODS Seventy-two female patients with PBC were evaluated prospectively. Clinical information, BMD assessment, disease severity, and osteoporosis risk factors were documented, and multivariate regression modeling was performed. RESULTS Twenty-four percent of the patients were osteoporotic at the lumbar spine and 32% at the femur. Severe bone loss (z score <-2.0) occurs 4 times more frequently in patients with PBC compared with controls. Body weight (P = 0.003) and postmenopausal status (P = 0.012) correlated independently with BMD. VDR genotype (P = 0.01) correlated with lower BMD at the spine only. CONCLUSIONS Osteoporosis is a common complication of PBC. VDR genotype predicts lower BMD in patients with PBC. Studies are warranted to investigate the mechanism(s) by which VDR as well as other candidate genes may contribute to the development of hepatic osteodystrophy in PBC.
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Affiliation(s)
- J E Springer
- Department of Medicine, University Health Network, University of Toronto, Ontario, Canada
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37
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Abstract
Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangiopathy are cholestatic liver diseases of unknown cause. Destruction of small to medium bile ducts (in primary biliary cirrhosis and autoimmune cholangiopathy) and large bile ducts (in primary sclerosing cholangitis) leads to progressive cholestasis, liver failure and end-stage liver disease. A variety of abnormalities in lipid metabolism have been described in primary biliary cirrhosis, and range from alterations in serum lipid levels and lipoprotein subsets to deranged metabolism of cholesterol. Progressive cholestasis and, consequently, decreased small intestinal bile acid concentrations in these cholestatic liver disease can also lead to impaired absorption of fats and fat-soluble vitamins, resulting in steatorrhea and deficiencies in vitamins A, D, E, and K. This article focuses on abnormalities in lipid metabolism in primary biliary cirrhosis and primary sclerosing cholangitis, and on lipid-activated vitamin deficiencies in these disorders.
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Affiliation(s)
- K V Kowdley
- Division of Gastroenterology and Hepatology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
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38
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Guañabens N, Parés A, Alvarez L, Martínez de Osaba MJ, Monegal A, Peris P, Ballesta AM, Rodés J. Collagen-related markers of bone turnover reflect the severity of liver fibrosis in patients with primary biliary cirrhosis. J Bone Miner Res 1998; 13:731-8. [PMID: 9580479 DOI: 10.1359/jbmr.1998.13.4.731] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The influence of a nonskeletal disease with increased connective tissue synthesis or degradation in the collagen-related markers of bone turnover has been evaluated in 34 women with primary biliary cirrhosis (PBC; age range 41-81 years), a disease with increased hepatic fibrosis, often associated with osteoporosis. Serum osteocalcin (BGP), and carboxy-terminal (PICP) and amino-terminal (PINP) propeptides of type I collagen were assessed as indexes of bone formation, whereas serum tartrate-resistant acid phosphatase (TRAP), and cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), and urinary hydroxyproline (HYP), pyridinoline (PYR), deoxypyridinoline (DPYR), and type I collagen cross-linked N- (NTX) and C-telopeptide (CTX) were measured as markers of bone resorption. The histologic stage of the disease and serum amino-terminal propeptide of type III collagen (PIIINP) as an index of liver fibrogenesis were also evaluated. BGP levels were significantly lower, whereas PICP and PINP levels were higher in patients than in controls. Among the bone resorption markers, serum ICTP and urinary PYR, DPYR, HYP, NTX, and CTX levels were significantly higher in patients than in controls. Serum PIIINP levels were also increased in PBC patients. BGP did not correlate with PICP and PINP, but these markers of bone formation as well as ICTP, PYR, DPYR, and NTX correlated with serum PIIINP levels. Serum TRAP did not correlate with collagen-related markers of bone resorption. Moreover, patients with PIIINP and bilirubin above normal levels had higher PICP, PINP, ICTP PYR, DPYR, CTX, and NTX. These markers correlated with the histologic stage of the disease, but not with osteopenia measured by densitometric procedures in 22 patients. In conclusion, collagen-related markers of bone turnover do not reflect bone remodeling in PBC. The close association of these markers with PIIINP and the clinical and histologic stage of the liver disease suggests that they are influenced by liver collagen metabolism.
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Affiliation(s)
- N Guañabens
- Metabolic Bone Diseases Unit, Hospital Clínic i Provincial, University of Barcelona, Spain
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39
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Abstract
Osteopenia in the form of osteoporosis is a common clinical problem associated with chronic cholestatic liver disease, and clinical morbidity from atraumatic fractures is increasing as more patients with PBC and PSC undergo successful liver transplantation. In the absence of symptomatic fractures, the clinical diagnosis may not be evident and must be sought by specific means to assess bone mineral density. The clinical problem has now been defined, but much remains unknown, from etiologic mechanisms to effective therapies. At present, it seems reasonable to provide aggressive supportive therapy in an attempt to maximize skeletal well-being until more effective therapies for osteopenia become available.
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Affiliation(s)
- J E Hay
- Mayo Clinic, Rochester, Minnesota
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40
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41
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Shiomi S, Kuroki T, Masaki K, Takeda T, Nishiguchi S, Nakajima S, Seki S, Kobayashi K, Okamura T, Ochi H. Osteopenia in primary biliary cirrhosis and cirrhosis of the liver in women, evaluated by dual-energy X-ray absorptiometry. J Gastroenterol 1994; 29:605-9. [PMID: 8000509 DOI: 10.1007/bf02365443] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
To study bone involvement in primary biliary cirrhosis (PBC), we used dual-energy X-ray absorptiometry to measure bone mineral density (BMD) in Japanese women with PBC and with cirrhosis of the liver. In both groups, in each decade up to 60 years of age, the mean BMD of the lumbar spine was not significantly different from that in healthy Japanese women; however, in patients aged 60 years or more, the level was significantly lower both in the patients with PBC (P < 0.001) and in those with cirrhosis of the liver (P < 0.01). Patients with PBC were also examined by single-photon absorptiometry. The BMD of the radius in the patients with PBC was less changed than that of the lumbar vertebrae; thus, the bone changes in PBC seem to be greater in spongy than in cortical bone.
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Affiliation(s)
- S Shiomi
- Third Department of Internal Medicine, Osaka City University Medical School, Japan
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42
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Guañabens N, Parés A, del Rio L, Roca M, Gómez R, Muñoz J, Rodés J. Sodium fluoride prevents bone loss in primary biliary cirrhosis. J Hepatol 1992; 15:345-9. [PMID: 1447501 DOI: 10.1016/0168-8278(92)90066-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Low-bone-turnover osteoporosis is a common complication of primary biliary cirrhosis (PBC). Since sodium fluoride stimulates bone formation we assessed the effect of this drug on bone mass in a 2-year, prospective, double-blind trial including 22 women with PBC who were randomly assigned to receive sodium fluoride (50 mg/day) or placebo. All received calcium supplements and low doses of vitamin D. Bone mineral density of the lumbar spine was measured by dual-photon absorptiometry initially and every 6 months. Vertebral fractures were evaluated in thoracic and lumbar spine initially, and after 1 and 2 years. Seven patients in the fluoride group and eight in the placebo group completed the trial. In the fluoride group, bone mineral density did not change after 2 years (initial 1.05 +/- 0.07, final 1.07 +/- 0.06 g/cm2; p = n.s.). In the placebo group, however, bone mineral density decreased significantly (initial 1.00 +/- 0.07, final 0.93 +/- 0.06 g/cm2; p = 0.03). Moreover, in the fluoride group bone mineral density increased by 2.9 +/- 3.6%, and in the placebo group decreased by 6.6 +/- 2.6% (p = 0.04). None of the patients developed new vertebral or non-vertebral fractures. Treatment with sodium fluoride did not impair liver function or cholestasis in PBC. These results indicate that sodium fluoride prevents bone loss in PBC and therefore might be considered as a possible therapeutic agent for osteoporosis associated with this liver disease. Since a small number of patients completed the trial, further studies are required.
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Affiliation(s)
- N Guañabens
- Service of Rheumatology, Hospital Clinic i Provincial, University of Barcelona, Spain
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43
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Gonchoroff DG, Branum EL, Cedel SL, Riggs BL, O'Brien JF. Clinical evaluation of high-performance affinity chromatography for the separation of bone and liver alkaline phosphatase isoenzymes. Clin Chim Acta 1991; 199:43-50. [PMID: 1934501 DOI: 10.1016/0009-8981(91)90007-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The newly described high-performance (HPLC) affinity chromatography method for the separation of human bone and liver alkaline phosphatase (ALP, EC 3.1.3.1) isoenzymes was clinically evaluated. The improved resolution of bone from liver isoenzyme and lower detection limit was achieved by conjugation of wheat-germ lectin (WGL) to a diol-bonded silica gel column, stepwise elution with N-acetylglucosamine (NAG) and post column derivatization using para-nitrophenyl phosphate substrate. To establish a reference interval, we measured bone ALP in 86 healthy women, ages 33 to 95 years. The normal reference interval is described by a piecewise linear regression on age (R2 = 0.20, P less than 0.01). For women less than or equal to 45 years, bone ALP, U/l = 8.495. For normal women between ages of 45 to 55 years, bone ALP, U/l = -12.765 + 0.472* age. If age greater than or equal to 55 years, then bone ALP, U/l 13.219. In all 10 patients with primary biliary cirrhosis, serum bone ALP levels were elevated. In addition, sera from 43 patients with diverse metabolic bone diseases were evaluated. As expected, the sera from all 6 patients with Paget's disease and 2 with osteolytic metastasis had bone ALP activity which was greater than 3 standard deviations (SD) from the mean. In all 10 patients with hypoparathyroidism, bone ALP levels were depressed. Only 1 of the 9 patients with glucocorticoid excess and 2 of the 7 patients with primary hyperparathyroidism had elevated bone ALP when compared to the 95% confidence interval for the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- D G Gonchoroff
- Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905
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44
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Floreani A, Chiaramonte M, Giannini S, Malvasi L, Lodetti MG, Castrignano R, Giacomini A, D'Angelo A, Naccarato R. Longitudinal study on osteodystrophy in primary biliary cirrhosis (PBC) and a pilot study on calcitonin treatment. J Hepatol 1991; 12:217-23. [PMID: 2051000 DOI: 10.1016/0168-8278(91)90941-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The aims of this study were to evaluate bone metabolism in primary biliary cirrhosis (PBC) and the effect of ADFR (activate, depress, free, repeat) therapy with vitamin D, calcium and calcitonin in preventing bone resorption. Sixty-nine female subjects entered the study: 38 PBC (AMA + ve) patients, 11 AMA-negative chronic liver disease patients and 20 age-matched healthy controls. Bone metabolism was evaluated by biochemical parameters and dual-photon absorptiometry of the lumbar spine at time 0, 6 and 18 months. Both PBC and chronic liver disease (CLD) patients showed low levels of serum 25-hydroxyvitamin D, osteocalcin and bone mineral content expressed as AAD (average area density) compared to healthy controls. Serum parathyroid hormone in PBC patients was at the lower limit of the normal range and was significantly lower than patients with chronic liver disease. At a 6-month interval, AAD significantly decreased in PBC patients (p less than 0.005). At the 6-month period PBC patients were allocated into two groups according to a cut-off AAD of 0.800 g/cm2: group A (no treatment, AAD greater than 0.800, n = 11), group B (treatment, AAD less than 0.800, n = 13). The latter group received a 4-week course with oral calcium carbonate (1500 mg daily) + oral 1,25-dihydroxyvitamin D (0.5 micrograms twice a day for 5 days) + carbocalcitonin (40 U MRC) i.m. thrice a week. The treatment was repeated with the same protocol at 2-month intervals for 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- A Floreani
- Department of Gastroenterology, University of Padova, Italy
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45
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Van Berkum FN, Beukers R, Birkenhäger JC, Kooij PP, Schalm SW, Pols HA. Bone mass in women with primary biliary cirrhosis: the relation with histological stage and use of glucocorticoids. Gastroenterology 1990; 99:1134-9. [PMID: 2394334 DOI: 10.1016/0016-5085(90)90635-e] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
To assess the impact of primary biliary cirrhosis on bone mass in general and the relative importance of the stage of the liver disease and of treatment with glucocorticoids for the possible development of osteoporosis, bone mineral mass was measured by single and dual photon absorptiometry in 55 unselected female patients with longstanding primary biliary cirrhosis. Although most of the patients had a bone mineral density within the normal range, the bone mineral densities of the lumbar spine and distal and proximal forearm were 8% (P less than 0.004), 8% (P less than 0.03), and 5% (NS) respectively, lower than in age-matched healthy women. Multiple regression analysis showed that the histological stage of the liver disease (early stage vs. late stage) was an independent determinant of axial bone mineral density, whereas the use of glucocorticoids resulted in only a moderate and not significant bone loss. Serum calcium proved to be significantly lower in the patients with late-stage primary biliary cirrhosis than in those with early-stage disease, whereas no significant differences were found in these groups with regard to several biochemical parameters of bone metabolism. In conclusion, in patients with primary biliary cirrhosis, bone loss was only moderate and related to the histological stage. The effect of low-dose glucocorticoids on bone mass seemed not significant.
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Affiliation(s)
- F N Van Berkum
- Department of Internal Medicine III, University Hospital Rotterdam, Dijkzigt, Erasmus University, The Netherlands
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46
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Cornell RP. Acute phase responses after acute liver injury by partial hepatectomy in rats as indicators of cytokine release. Hepatology 1990; 11:923-31. [PMID: 2114349 DOI: 10.1002/hep.1840110604] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The purpose of this study was to support the hypothesis that cytokines such as interleukin-1, tumor necrosis factor and interleukin-6 are released by macrophages or monocytes within 1 to 2 hr of phagocytosis of circulating, gut-derived bacterial lipopolysaccharide translocated by acute liver injury. Time courses of fever, neutrophilia and low blood-zinc levels generally attributed to cytokines were quantified after partial (67%) hepatectomy of rats under ether anesthesia. These acute phase responses in hepatectomized rats were compared with those after intravenous injection of exogenous endotoxin and human natural interleukin-1. Fever commenced 30 min after interleukin-1 injection, 4 hr after exogenous lipopolysaccharide injection and 6 hr after 67% liver resection. Similarly, rectal temperatures were significantly elevated in recipient rats 30 min after intravenous administration of donor plasma from hepatectomized animals, indicating that cytokines, not lipopolysaccharide, elicited the febrile response. Neutrophilia was present 1, 2, and 4 hr after interleukin-1 injection, lipopolysaccharide injection and hepatectomy, respectively. Furthermore, the reduction in plasma zinc, which depends on cellular metallothionein synthesis, occurred 4 hr after interleukin-1 administration and 6 hr after lipopolysaccharide injection or partial hepatectomy. Donor plasma from hepatectomized rats also elicited neutrophilia at 1 hr and low blood-zinc levels 4 hr after injection in recipient animals. The timing of these responses, just as for the fever, implies that cytokines and not lipopolysaccharide in the donated plasma elicited the neutrophilia and hypozincemia. Evidence was reviewed that interleukin-1, tumor necrosis factor and interleukin-6 function as hepatotrophic factors and have been identified in the circulation of humans with liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- R P Cornell
- Division of Science, Northeast Missouri State University, Kirksville 63501
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47
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Affiliation(s)
- T H Diamond
- Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
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48
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Diamond T, Stiel D, Lunzer M, Wilkinson M, Roche J, Posen S. Osteoporosis and skeletal fractures in chronic liver disease. Gut 1990; 31:82-7. [PMID: 2318434 PMCID: PMC1378345 DOI: 10.1136/gut.31.1.82] [Citation(s) in RCA: 158] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In order to determine the prevalence and severity of hepatic osteodystrophy by non-invasive means we compared 115 consecutive ambulant patients with histologically proven chronic liver disease to 113 age and sex matched control subjects. Methods used included the assessment of fracture prevalence rates, spinal radiography, and measurements of bone mineral density in the spine and the forearm. Spinal and peripheral fractures were more prevalent in the patients than in the control subjects (p less than 0.03 and p less than 0.01 respectively). The type of the underlying liver disease did not significantly affect the fracture prevalence rates, but alcoholic patients sustained more peripheral fractures than patients with other hepatic disorders (p less than 0.05). The bone mineral densities of the spines and the forearms were significantly reduced in male patients of all age groups and in female patients aged 60 years or more (p less than 0.001 for men and p less than 0.01 for women for both measurements). The prevalence rates of spinal and forearm osteoporosis were twice as high among patients with liver disease than in control subjects regardless of the definitions used. The presence of cirrhosis and hypogonadism were major risk factors for development of both spinal (Beta coef = 0.190 and 0.176; SE = 0.079 and 0.086 respectively) and forearm osteoporosis (Beta coef = 0.20 and 0.29; SE = 0.073 and 0.80 respectively). Spinal bone density was the predominant determinant of spinal fractures (Beta coef = -0.007; SE = 0.001), while hypogonadism (Beta coef = 0.363; SE = 0.075) and cirrhosis (Beta coef = 0.185; SE = 0.068) were the major predictors of peripheral fractures. The concentrations of serum calcium and serum vitamin D metabolites and the use of corticosteroids were apparently without effect on the prevalence of skeletal fractures or bone density.
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Affiliation(s)
- T Diamond
- Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Sydney, Australia
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49
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Mitchison HC, Bassendine MF, Malcolm AJ, Watson AJ, Record CO, James OF. A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology 1989; 10:420-9. [PMID: 2777203 DOI: 10.1002/hep.1840100405] [Citation(s) in RCA: 105] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
A randomized, double-blind, 1-year pilot study of prednisolone treatment for primary biliary cirrhosis was undertaken. Nineteen patients received 30 mg prednisolone per day initially, with a maintenance dose of 10 mg per day. Seventeen patients received placebo. The groups were matched for age, menopausal status, hepatic histological stage and bilirubin. Treatment was well tolerated without dropouts. Two patients receiving prednisolone developed diabetes, one a duodenal ulcer and one depression. One patient receiving placebo died for liver failure after 3 months. Cholestatic symptoms (itch and fatigue) improved on prednisolone. There was significant (prednisolone vs. placebo) improvement in transaminase (p = 0.0214), alkaline phosphatase (p = 0.0032), procollagen III peptide (p = 0.0103), immunoglobulin G (p = 0.0012) and liver histology (p = 0.016); these changes were greatest among noncirrhotic patients. No patient developed skeletal symptoms. Fifty-seven per cent had abnormal triolein breath tests prior to treatment, and 65% had abnormally low calcium absorption tests. Calcium absorption increased significantly in the treated group vs. placebo at 2 weeks (p less than 0.02), but not at 1 year. Femoral photon absorptiometry fell in the prednisolone group after 1 year (-3.5% vs. placebo +0.5%, p less than 0.05), as did trabecular bone volume (-6% vs. -2.8%, p less than 0.005) and resorption surface (-11% vs. +2%, p less than 0.02) on serial bone biopsy. Prednisolone seems to exert a favorable hepatic effect in primary biliary cirrhosis but at the expense of increased bone loss to approximately twice the expected rate. Prednisolone treatment merits further assessment in primary biliary cirrhosis over a longer period, with attention to selection of patients most likely to benefit and continuing observation of bone mass to better establish the "cost/benefit" ratio.
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Affiliation(s)
- H C Mitchison
- Department of Medicine, University of Newcastle Upon Tyne, United Kingdom
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50
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Abstract
Primary biliary cirrhosis is a chronic liver disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to an inflammatory destruction of small intrahepatic bile ducts. The clinical course of PBC is variable ranging from a few years in rapidly progressive cases to a normal life-expectancy in a proportion of asymptomatic cases. The typical patient is a middle-aged woman who may present with pruritus, increasing pigmentation of the skin, and eventually jaundice. The level of serum alkaline phosphatase is almost invariably elevated, serum mitochondrial antibodies are present in more than 90 per cent, and an elevated serum IgM is usually present. PBC is associated with many immunologic abnormalities and appears to be a classic autoimmune disease. Some of the immune defects may be epiphenomena; others such as a marked defect in suppressor T cell function seem to be related to the pathogenesis of the disease. All drug therapy that is aimed at slowing the disease process is experimental. A place for immunosuppressive drugs in the management of PBC would be anticipated. However, no drug has to date been definitively shown to have a beneficial effect on the disease. Currently, the main treatments used are aimed at preventing or correcting the complications of intractable cholestasis. Patients with PBC and evidence of hepatic decompensation and/or poor quality of life make good candidates for liver transplantation. The current aim of therapy is to find an effective regime of immunosuppression that will make hepatic transplantation redundant for this disease.
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Affiliation(s)
- R Moreno-Otero
- Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases, Bethesda, Maryland
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