|
1
|
Ebeling PR, Nguyen HH, Aleksova J, Vincent AJ, Wong P, Milat F. Secondary Osteoporosis. Endocr Rev 2022; 43:240-313. [PMID: 34476488 DOI: 10.1210/endrev/bnab028] [Citation(s) in RCA: 155] [Impact Index Per Article: 51.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Indexed: 02/07/2023]
Abstract
Osteoporosis is a global public health problem, with fractures contributing to significant morbidity and mortality. Although postmenopausal osteoporosis is most common, up to 30% of postmenopausal women, > 50% of premenopausal women, and between 50% and 80% of men have secondary osteoporosis. Exclusion of secondary causes is important, as treatment of such patients often commences by treating the underlying condition. These are varied but often neglected, ranging from endocrine to chronic inflammatory and genetic conditions. General screening is recommended for all patients with osteoporosis, with advanced investigations reserved for premenopausal women and men aged < 50 years, for older patients in whom classical risk factors for osteoporosis are absent, and for all patients with the lowest bone mass (Z-score ≤ -2). The response of secondary osteoporosis to conventional anti-osteoporosis therapy may be inadequate if the underlying condition is unrecognized and untreated. Bone densitometry, using dual-energy x-ray absorptiometry, may underestimate fracture risk in some chronic diseases, including glucocorticoid-induced osteoporosis, type 2 diabetes, and obesity, and may overestimate fracture risk in others (eg, Turner syndrome). FRAX and trabecular bone score may provide additional information regarding fracture risk in secondary osteoporosis, but their use is limited to adults aged ≥ 40 years and ≥ 50 years, respectively. In addition, FRAX requires adjustment in some chronic conditions, such as glucocorticoid use, type 2 diabetes, and HIV. In most conditions, evidence for antiresorptive or anabolic therapy is limited to increases in bone mass. Current osteoporosis management guidelines also neglect secondary osteoporosis and these existing evidence gaps are discussed.
Collapse
Affiliation(s)
- Peter R Ebeling
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia
| | - Hanh H Nguyen
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Department of Endocrinology and Diabetes, Western Health, Victoria 3011, Australia
| | - Jasna Aleksova
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Amanda J Vincent
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria 3168, Australia
| | - Phillip Wong
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Frances Milat
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| |
Collapse
|
|
2
|
Sarkar M, Brady CW, Fleckenstein J, Forde KA, Khungar V, Molleston JP, Afshar Y, Terrault NA. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 73:318-365. [PMID: 32946672 DOI: 10.1002/hep.31559] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Monika Sarkar
- University of California, San Francisco, San Francisco, CA
| | | | | | | | | | - Jean P Molleston
- Indiana University and Riley Hospital for Children, Indianapolis, IN
| | - Yalda Afshar
- University of California, Los Angeles, Los Angeles, CA
| | - Norah A Terrault
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| |
Collapse
|
|
3
|
Danford CJ, Ezaz G, Trivedi HD, Tapper EB, Bonder A. The Pharmacologic Management of Osteoporosis in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis. J Clin Densitom 2020; 23:223-236. [PMID: 31146965 DOI: 10.1016/j.jocd.2019.05.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/06/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Osteoporosis is a common complication of primary biliary cholangitis (PBC) yet evidence for effective therapy is lacking. We sought to review all randomized controlled trials evaluating pharmacotherapy against placebo or no intervention for treatment of osteoporosis in PBC. METHODOLOGY A comprehensive database search was conducted from inception through 29 March 2017. The primary outcome was incidence of fractures; secondary outcomes were change in bone mineral density (BMD) and adverse events. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same drug class. RESULTS We identified 11 randomized controlled trials evaluating bisphosphonates (3), hormone replacement therapy (2), ursodeoxycholic acid (1), obeticholic acid (1), cyclosporin A (1), vitamin K (1), calcitriol (1), and sodium fluoride (1). No intervention significantly reduced fractures compared to control. Although significant improvement in BMD was seen in one study with alendronate, a third-generation bisphosphonate, no significant improvement was seen on pooled analysis of all bisphosphonates including first-generation bisphosphonates (standard mean difference 0.41, p = 0.68). On pooled analysis, hormone replacement therapy modestly improved lumbar BMD (standard mean difference 0.69, p = 0.02), but with significantly increased adverse events (odds ratio 8.82, p = 0.01). CONCLUSIONS There is a lack of high-quality evidence supporting the efficacy of any treatment of osteoporosis in PBC. This may be explained by lack of power in the included studies. However, our current understanding of PBC-related osteoporosis indicates that it results from decreased bone formation, which may explain the attenuated effect of traditional antiresorptive agents. Future studies should investigate newer anabolic bone agents.
Collapse
Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Ghideon Ezaz
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
4
|
Danford CJ, Trivedi HD, Bonder A. Bone Health in Patients With Liver Diseases. J Clin Densitom 2020; 23:212-222. [PMID: 30744928 DOI: 10.1016/j.jocd.2019.01.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 12/19/2022]
Abstract
Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.
Collapse
Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA.
| |
Collapse
|
|
5
|
Trivedi HD, Danford CJ, Goyes D, Bonder A. Osteoporosis in Primary Biliary Cholangitis: Prevalence, Impact and Management Challenges. Clin Exp Gastroenterol 2020; 13:17-24. [PMID: 32021374 PMCID: PMC6970242 DOI: 10.2147/ceg.s204638] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 12/31/2019] [Indexed: 12/11/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic condition associated with symptoms that directly impact the quality of life in those afflicted with the disease. In addition to pruritus and fatigue, patients with PBC may develop metabolic bone disease from reduced bone density, such as osteopenia and osteoporosis. Osteoporosis increases the risk of fractures, as well as morbidity and mortality. The prevalence of osteoporosis in PBC is expected to increase in conjunction with the rising prevalence of PBC as a whole. Timely diagnosis, prevention and management of osteoporosis are crucial in order to optimize the quality of life. There is a paucity of data evaluating the management of osteoporosis in PBC. The optimal timing for diagnosis and monitoring is not yet established and is guided by expert opinion. National guidelines recommend screening for osteoporosis at the time of diagnosis of PBC. Monitoring strategies are based on results of initial screening and individual risk factors for bone disease. Identifying reduced bone density is imperative to institute timely preventive and treatment strategies. However, treatment remains challenging as efficacious therapies are currently lacking. The data on treatment of osteoporosis in PBC are mostly extrapolated from postmenopausal osteoporosis literature. However, this data has not directly translated to useful treatment strategies for PBC-related osteoporosis, partly because of the different pathophysiological mechanisms of the two diseases. The lack of useful preventive measures and efficacious treatment strategies remains the largest pitfall that challenges the management of patients with PBC. In this review, we comprehensively outline the epidemiology, clinical implications and challenges, as well as management strategies of PBC-related osteoporosis.
Collapse
Affiliation(s)
- Hirsh D Trivedi
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christopher J Danford
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Daniela Goyes
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alan Bonder
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
6
|
Gerussi A, Cristoferi L, Carbone M, Asselta R, Invernizzi P. The immunobiology of female predominance in primary biliary cholangitis. J Autoimmun 2018; 95:124-132. [DOI: 10.1016/j.jaut.2018.10.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 10/17/2018] [Indexed: 12/21/2022]
|
|
7
|
Danford CJ, Trivedi HD, Papamichael K, Tapper EB, Bonder A. Osteoporosis in primary biliary cholangitis. World J Gastroenterol 2018; 24:3513-3520. [PMID: 30131657 PMCID: PMC6102495 DOI: 10.3748/wjg.v24.i31.3513] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/11/2018] [Accepted: 07/21/2018] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with multiple debilitating complications. Osteoporosis is a common complication of PBC resulting in frequent fractures and leading to significant morbidity in this population, yet evidence for effective therapy is lacking. We sought to summarize our current understanding of the pathophysiology of osteoporosis in PBC, as well as current and emerging therapies in order to guide future research directions. A complete search with a comprehensive literature review was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, and the Countway Library. Osteoporosis in PBC is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Despite this fundamental difference, current treatment recommendations are based primarily on experience with postmenopausal osteoporosis. Trials specific to PBC-related osteoporosis are small and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in PBC relies on the mitigation of risk factors such as smoking and alcohol use, as well as encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in PBC remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in PBC and summarizes current and emerging therapies.
Collapse
Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Konstantinos Papamichael
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Elliot B Tapper
- Department of Hepatology, University of Michigan, Ann Arbor, MI 48109, Unites States
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
Abstract
Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease that primarily affects women (female-to-male ratio, 10:1) between 40 and 60 years of age. Metabolic bone disease is a common complication of PBC, affecting 14% to 52% of patients, depending on the duration and severity of liver disease. The osteoporosis seen in PBC seems mainly due to low bone formation, although increased bone resorption may contribute. Treatment of osteoporosis consists primarily of antiresorptive agents. Additional large prospective, long-term studies in patients with PBC are needed to determine efficacy in improving bone density as well as reducing fracture risk.
Collapse
Affiliation(s)
- Lisa M Glass
- Gastroenterology Section, Department of Internal Medicine, VA Ann Arbor Health Care System, University of Michigan Health System, 2215 Fuller Road, Ann Arbor, MI 48105, USA
| | - Grace Li-Chun Su
- Gastroenterology Section, Specialty Care and Access, VA Ann Arbor Health Care System, University of Michigan Medical School, 2215 Fuller Road, Ann Arbor, MI 48105, USA.
| |
Collapse
|
|
10
|
Li DL, Liu BR. A review of differences in cirrhosis between men and women and characteristics of cirrhosis in females. Shijie Huaren Xiaohua Zazhi 2015; 23:1763-1769. [DOI: 10.11569/wcjd.v23.i11.1763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There are differences in the disease susceptibility, natural history of liver disease, complications and treatment response between females and males with cirrhosis. Pre-menopausal status for female patients is protective against viral hepatitis C, non-alcoholic steatohepatitis and primary biliary cirrhosis. Smoking accompanied with drinking is a strong risk factor for cirrhosis and malignancies in women with chronic liver disease. Pregnancy increases the incidence of variceal hemorrhage and hepatic encephalopathy in patients with cirrhosis. The choice of contraceptive measures between patients with liver cirrhosis and normal people is the same. The selection of drugs and surgical treatment in female patients with liver cirrhosis before and after pregnancy complications have obvious differences. The organ distribution of model for end-stage liver disease (MELD) scoring system is detrimental to female patients, but the introduction of new drugs for viral hepatitis C is expected to change this difference.
Collapse
|
|
11
|
Marchioni Beery RM, Vaziri H, Forouhar F. Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis: a Review Featuring a Women's Health Perspective. J Clin Transl Hepatol 2014; 2:266-84. [PMID: 26357630 PMCID: PMC4521232 DOI: 10.14218/jcth.2014.00024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 10/15/2014] [Accepted: 10/19/2014] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are two major types of chronic cholestatic liver disease. Each disorder has distinguishing features and variable progression, but both may ultimately result in cirrhosis and hepatic failure. The following offers a review of PBC and PSC, beginning with a general overview of disease etiology, pathogenesis, diagnosis, clinical features, natural course, and treatment. In addition to commonly associated manifestations of fatigue, pruritus, and fat-soluble vitamin deficiency, select disease-related topics pertaining to women's health are discussed including metabolic bone disease, hyperlipidemia and cardiovascular risk, and pregnancy-related issues influencing maternal disease course and birth outcomes. This comprehensive review of PBC and PSC highlights some unique clinical considerations in the care of female patients with cholestatic liver disease.
Collapse
Affiliation(s)
- Renée M. Marchioni Beery
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Renée M. Marchioni Beery, DO, Division of Internal Medicine, Department of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-1845, USA. Tel: +01-860-679-3158, Fax: +01-860-679-3159. E-mail:
| | - Haleh Vaziri
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - Faripour Forouhar
- Department of Pathology and Lab Medicine, University of Connecticut Health Center, Farmington, CT, USA
| |
Collapse
|
|
12
|
Allen AM, Hay JE. Review article: the management of cirrhosis in women. Aliment Pharmacol Ther 2014; 40:1146-54. [PMID: 25263269 DOI: 10.1111/apt.12974] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 07/21/2014] [Accepted: 09/09/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND There are differences in the predisposition, natural history of liver disease, complications and treatment response between men and women. AIM To review clinical differences in cirrhosis between men and women and to address unique management issues of fertility, pregnancy and contraception in this patient population. METHODS PubMed and MEDLINE were searched using the terms 'cirrhosis' and 'chronic liver disease', each cross-referenced with specific liver diseases, as well as terms such as 'cancer', 'hepatocellular carcinoma', 'smoking', 'liver transplantation', 'metabolic bone disease', 'fertility',' pregnancy' and 'contraception'. RESULTS Pre-menopausal status is protective in viral hepatitis C and non-alcoholic steatohepatitis. However, smoking, especially in combination with alcohol, is a stronger risk factor for cirrhosis and malignancies in women with chronic liver disease compared to men, although they are less likely than men to develop hepatocellular carcinoma. Women with cirrhosis have more osteopenic bone disease than men and require active management. Successful pregnancy is possible in well-compensated cirrhosis or with mild portal hypertension, although the maternal and foetal mortality and morbidity are higher than in the general population. The maternal risk correlates with liver disease severity and derives mostly from variceal bleeding. The choices for contraception in compensated cirrhosis are generally the same as for the general population. Women with cirrhosis are disadvantaged by the current MELD system of organ allocation, at least in part due to body size. CONCLUSION The management of women with chronic liver disease is unique in regards to counselling, screening for complications, fertility and pregnancy.
Collapse
Affiliation(s)
- A M Allen
- Hepatology and Liver Transplantation, Mayo Clinic, Rochester, MN, USA
| | | |
Collapse
|
|
13
|
Carey EJ, Lindor KD. Current pharmacotherapy for cholestatic liver disease. Expert Opin Pharmacother 2012; 13:2473-84. [PMID: 23094715 DOI: 10.1517/14656566.2012.736491] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPORTANCE OF THE FIELD The cholestatic liver diseases comprise a heterogeneous group of disorders which, left untreated, usually progresses to cirrhosis and liver failure. Most are recognized before the onset of advanced fibrosis, thereby affording an opportunity for disease modifying therapy. AREAS COVERED This review will cover the current pharmacologic management of the most common causes of cholestatic liver disease in adults, including primary biliary cirrhosis, primary biliary cirrhosis-autoimmune hepatitis overlap syndrome, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, intestinal failure-associated liver disease, and immunoglobulin G4-associated cholangitis. Pharmacologic management of complications of cholestasis will also be reviewed. EXPERT OPINION Effective therapy for most cholestatic liver disease is lacking. Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis but the majority of patients do not have a full response. Even in those with a complete response, UDCA does not cure the disease. There is currently no effective medical therapy for primary sclerosing cholangitis. Symptoms and serum liver biochemistry values in intrahepatic cholestasis of pregnancy are improved with UDCA, but it is not certain if this alters the course of disease. Immunoglobulin G4-associated cholangitis is responsive to steroids but may relapse. The farnesoid X receptor agonists are a promising new class of drugs currently being tested in cholestatic liver disease.
Collapse
Affiliation(s)
- Elizabeth J Carey
- Mayo Clinic in Arizona, Division of Hepatology, Phoenix, AZ 85054, USA.
| | | |
Collapse
|
|
14
|
Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Hormone replacement for osteoporosis in women with primary biliary cirrhosis. Cochrane Database Syst Rev 2011:CD009146. [PMID: 22161447 DOI: 10.1002/14651858.cd009146.pub2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Women with primary biliary cirrhosis often suffer from postmenopausal osteoporosis due to their age, or osteoporosis secondary to their liver disease, or treatments provided for their liver disease. Hormone replacement increases bone mineral density and reduces fractures in postmenopausal women. On the other hand, hormone replacement increases the risk of various adverse events. We could not identify any meta-analyses or systematic reviews on hormone replacement in women with primary biliary cirrhosis. OBJECTIVES To assess the beneficial and harmful effects of hormone replacement for osteoporosis in women with primary biliary cirrhosis. SEARCH METHODS The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. Manufacturers and authors were contacted during the review conductance. SELECTION CRITERIA All randomised clinical trials of hormone replacement in primary biliary cirrhosis administered by any route, or regimen, or dose compared with placebo or no intervention. DATA COLLECTION AND ANALYSIS Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD), all with 95% confidence intervals (CI). Methodological domains were used to assess risk of systematic errors (bias). Trial sequential analysis was used to control for random errors (play of chance). MAIN RESULTS Two trials with 49 participants were included. One trial had low risk of bias. The other trial had high risk of bias. Hormone replacement had no effect on all-cause mortality (RD 0.00; 95% CI -0.11 to 0.11, I² = 0%) and fractures (RD -0.08; 95% CI -0.24 to 0.07, I² = 0%). Hormone replacement significantly increased adverse events and number of patients having hormone replacement withdrawn due to adverse events (RR 5.26; 95% CI 1.26 to 22.04, I² = 0%). Hormone replacement had no significant effect on lumbar spine bone mineral density (MD 1.25 g/cm² yearֿ¹; 95% CI -0.91 to 3.42, I² = 0%). On the other hand, a significant increase in proximal femur bone mineral density was observed in the control group (MD 2.24 g/cm² yearֿ¹; 95% CI 0.74 to 3.74, I² = 0%). Hormone replacement had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity. Hormone replacement had no significant effect on serum bilirubin concentration (MD 4.60 µmol/L; 95% CI -3.42 to 12.62, I² = 0%). AUTHORS' CONCLUSIONS We did not find evidence to support the use of hormone replacement for women with primary biliary cirrhosis. It seems that hormone replacement is connected with a significant increase in the occurrence of adverse events.
Collapse
Affiliation(s)
- Jelena S Rudic
- Department of Hepatology, Clinic of Gastroenterology, Clinical Centre of Serbia, Koste Todorovica 2, Belgrade, Serbia, 11000
| | | | | | | | | |
Collapse
|
|
15
|
Angulo P, Grandison GA, Fong DG, Keach JC, Lindor KD, Bjornsson E, Koch A. Bone disease in patients with primary sclerosing cholangitis. Gastroenterology 2011; 140:180-8. [PMID: 20955707 PMCID: PMC3043598 DOI: 10.1053/j.gastro.2010.10.014] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Revised: 09/30/2010] [Accepted: 10/07/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Osteopenic bone disease occurs frequently among patients with chronic liver disease but has not been well studied in those with primary sclerosing cholangitis (PSC). We investigated the prevalence, rate of progression, and independent predictors of bone disease in a large number of patients with all stages of PSC. METHODS Bone mineral density of the lumbar spine, hip, and total body was measured yearly for 10 years in 237 patients with PSC. RESULTS Osteoporosis (T-score less than -2.5) was found in 15% of patients and occurred 23.8-fold (95% confidence interval [CI], 4.6-122.8) more frequently in those with PSC than expected from a matched population. By multivariate analysis, age 54 years or older (odds ratio [OR], 7.8; 95% CI, 3.3-18.3), body mass index ≤ 24 kg/m(2) (OR, 4.9; 95% CI, 1.9-12.6), and inflammatory bowel disease for ≥ 19 years (OR, 3.6; 95% CI, 1.5-8.4) correlated with the presence of osteoporosis. Osteoporosis was present in 75% of patients with all 3 risk factors but in only 3.1% of those without all of them. Patients with PSC lost 1% of bone mass per year; this rate of bone loss was significantly associated with duration of inflammatory bowel disease. CONCLUSIONS Osteoporosis occurs frequently among patients with PSC. Old age, low body mass index, and long duration of inflammatory bowel disease can be used to identify patients with PSC who might derive the most benefit from measurements of bone density and treatments for bone diseases.
Collapse
Affiliation(s)
- Paul Angulo
- Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
| | | | | | | | | | | | | |
Collapse
|
|
16
|
Miheller P, Lakatos PL, Tóth M. Bone Homeostasis in Intestinal Disorders. Clin Rev Bone Miner Metab 2010; 8:140-148. [DOI: 10.1007/s12018-010-9069-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
17
|
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.
Collapse
|
|
18
|
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.
Collapse
Affiliation(s)
- Robert H Boone
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | | | | | | |
Collapse
|
|
19
|
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.
Collapse
Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
| | | |
Collapse
|
|
20
|
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.
Collapse
Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Munich, Germany
| | | |
Collapse
|
|
21
|
Uretmen S, Gol M, Cimrin D, Irmak E. Effects of chronic liver disease on bone mineral density and bone metabolism markers in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2005; 123:67-71. [PMID: 16051419 DOI: 10.1016/j.ejogrb.2005.06.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2004] [Revised: 06/27/2005] [Accepted: 06/29/2005] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Patients with chronic liver disease (CLD) have an increased prevalence of osteoporosis. However, there is limited information about the effects of end-stage liver disease on bone metabolism and bone mineral density values in postmenopausal women. The aim of this study was to investigate the effects of chronic liver disease on bone mineral density (BMD) and bone metabolism markers in postmenopausal women. METHODS We studied BMD by using dual-energy X-ray absorptiometry (DEXA), biochemical markers of bone turnover and calcium-parathyroid hormone (PTH)-Vitamin D axis in 22 postmenopausal women with CLD. Control group consisted of randomly recruited 30 healthy postmenopausal women. RESULTS Based on WHO criteria, the prevalence of osteoporosis was significantly higher in patients with CLD (72 versus 33%) compared to healthy postmenopausal women. Bone loss was more significant at the lumbar spine than femur in the study group. Urinary excretion of bone resorption marker deoxypyridinoline was increased significantly in patients with CLD. There were no significant differences in bone formation markers (osteocalcin and bone alkaline phosphatase) between the groups. CONCLUSIONS CLD increases the prevalence of osteoporosis in postmenopausal women, particularly in the lumbar spine. Increased bone resorption seems to be the main reason for osteoporosis in these patients. We suggest that treatment strategies should be improved in these women to protect them from subsequent fractures.
Collapse
Affiliation(s)
- Sevinc Uretmen
- Izmir Ataturk Research and Training Hospital, Department of Internal Medicine, Turkey
| | | | | | | |
Collapse
|
|
22
|
Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM, USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005; 42:1194-202. [PMID: 16250040 PMCID: PMC3150736 DOI: 10.1002/hep.20907] [Citation(s) in RCA: 438] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology, often associated with other autoimmune conditions. Controlled studies have so far provided conflicting data on risk factors and comorbidity rates in PBC. We enrolled patients with PBC (n = 1032) from 23 tertiary referral centers for liver diseases in the United States and random-digit-dialed controls (n = 1041) matched for sex, age, race, and geographical location. Patients and controls were administered a modified version of the US National Health and Nutrition Examination Study (NHANES III) questionnaire by trained personnel to evaluate associations between PBC and social, demographic, personal and family medical histories, lifestyle, and reproductive factors and the rates of comorbidity in affected individuals. Data indicate that having a first-degree relative with PBC (adjusted odds ratio [AOR] 10.736; 95% confidence interval 4.227-27.268), history of urinary tract infections (AOR 1.511, 95% CI 1.192-1.915), past smoking (AOR 1.569, 95% CI 1.292-1.905), or use of hormone replacement therapies (AOR 1.548, 95% CI 1.273-1.882) were significantly associated with increased risk of PBC. The frequent use of nail polish slightly increased the risk of having PBC. Other autoimmune diseases were found in 32% of cases and 13% of controls (P<0.0001). In conclusion, environmental factors, possibly including infectious agents through urinary tract infections or chemicals contained in cigarette smoke, may induce PBC in genetically susceptible individuals. Exogenous estrogens may also contribute to explain the female predominance of the disease.
Collapse
Affiliation(s)
- M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Abstract
This article discusses the clinical importance of hepatic osteopenia, the identification of risk factors for the individual patient, and the selection of patients, timing, and methods for diagnostic screening. General supportive measures to maximize bone health should be used in all patients at risk. In addition, for the patient with established osteoporosis, specific therapeutic measures may be justified, despite the lack of adequate randomized trials of these agents in patients with hepatic osteopenia.
Collapse
Affiliation(s)
- J Eileen Hay
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, Southwest, Rochester, MN 55905, USA.
| | | |
Collapse
|
|
24
|
Zein CO, Jorgensen RA, Clarke B, Wenger DE, Keach JC, Angulo P, Lindor KD. Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial. Hepatology 2005; 42:762-71. [PMID: 16175618 DOI: 10.1002/hep.20866] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than -1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 +/- 0.03 g/cm2 SD from baseline) compared with the placebo group (-0.003 +/- 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety.
Collapse
Affiliation(s)
- Claudia O Zein
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Affiliation(s)
- Marshall M Kaplan
- Division of Gastroenterology, Tufts-New England Medical Center, Boston, MA 02111, USA.
| | | |
Collapse
|
|
26
|
Li J, Liao EY, Dai RC, Wei QY, Luo XH. Effects of 17 beta-estradiol on the expression of interstitial collagenases-8 and -13 (MMP-8 and MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in ovariectomized rat osteoblastic cells. J Mol Histol 2005; 35:723-31. [PMID: 15609084 DOI: 10.1007/s10735-004-6206-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Estrogen plays an important role in maintaining normal bone metabolism via the direct or indirect regulation of bone cells. Osteoblastic cells, as the target cells of estrogen, can secrete multiple matrix metalloproteinases (MMPs) that participate in bone remodeling. It has been demonstrated that bone loss induced by estrogen deficiency is closely related to the abnormal expression of multiple MMPs in osteoblastic cells. However, the regulating action of estrogen on the expression of interstitial collagenases MMP-8 and MMP-13 in osteoblastic cells in vivo remains unclear. We used an ovariectomized osteoporotic rat model to analyze the changes in the histomorphometric parameters of bone after and without treatment with 17beta-estradiol (E(2)); We also used immunohistochemistry and in situ hybridization to observe changes in the expression of mRNA and the proteins MMP-8, MMP-13 and TIMP-1 in osteoblastic cells in rat proximal tibia. In this study, we found that in the ovariectomized rat the expression of MMP-13 mRNA and protein increased markedly, whereas the expression of MMP-8 and TIMP-1 mRNA and protein did not change significantly. Our analysis showed that the expression of MMP-13 protein was correlated positively to bone trabecular separation, osteoid surface area, and negatively to trabecular numbers and the percentage of trabecula bone volume/total tissue volume. Our results suggest that MMP-13 plays an important role in estrogen deficiency-induced bone loss, while estrogen can inhibit bone resorption and reduce bone turnover rate by down-regulating the expression of MMP-13 in osteoblastic cells.
Collapse
Affiliation(s)
- Jian Li
- Department of Pathology, Second Xiangya Hospital, Central South University, PR China
| | | | | | | | | |
Collapse
|
|
27
|
Ormarsdóttir S, Mallmin H, Naessén T, Petrén-Mallmin M, Broomé U, Hultcrantz R, Lööf L. An open, randomized, controlled study of transdermal hormone replacement therapy on the rate of bone loss in primary biliary cirrhosis. J Intern Med 2004; 256:63-9. [PMID: 15189367 DOI: 10.1111/j.1365-2796.2004.01342.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVES The prevalence of osteoporosis amongst patients with primary biliary cirrhosis (PBC) is high and may be a serious clinical problem. Hormone replacement therapy (HRT) is effective in preventing bone loss but has not been evaluated in randomized trials in PBC. The primary aim was to study the effect of transdermal HRT in combination with daily vitamin D and calcium supplementation on bone loss compared with vitamin D and calcium supplementation only in postmenopausal women with PBC. The secondary aim was to study the safety of transdermal HRT. SUBJECTS/INTERVENTIONS Eighteen females with PBC were randomized to receive 2 years therapy with either (i) transdermal oestradiol 50 microg 24 h(-1) two times per week + medroxyprogesterone 2.5 mg day(-1) + alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1) or (ii) alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1). Dual-energy X-ray absorptiometry for measurement of bone mineral density (BMD) and sampling of blood and serum for measurements of biochemical markers of liver function was performed before, during and at the end of treatment. RESULTS BMD increased significantly at the lumbar spine (P < 0.05) and the femoral neck (P < 0.05) in the HRT group whereas no significant change was found in the control group. One oestrogen-treated patient was excluded after 1 year because of deteriorating, but reversible, aminotransferases. Dropout frequency because of nonliver-related causes was higher in the HRT group. Otherwise, no difference with respect to adverse liver reactions was found between the groups. CONCLUSION Transdermal HRT increases BMD in PBC patients with few severe side effects related to the liver.
Collapse
Affiliation(s)
- S Ormarsdóttir
- Internal Medicine, Institution for Medical Sciences, University Hospital, Uppsala, Sweden.
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
PURPOSE OF REVIEW This review highlights recent developments in the molecular pathogenesis of cholestasis as well new aspects of pathogenesis and management of clinical cholestatic disorders. RECENT FINDINGS Highlights include the role of nuclear receptors including FXR ligands as potential therapeutic agents, new genetic defects for pediatric cholestasis and sclerosing cholangitis, and novel infections and environmental agents as etiologies for primary biliary cirrhosis. Important clinical studies have been published in the area of pediatric cholestatic syndromes, intrahepatic cholestasis of pregnancy, primary biliary cirrhosis, primary and secondary sclerosing cholangitis, cholestasis of sepsis, viral cholestatic syndromes, and drug-induced cholestasis. SUMMARY These advances continue to improve understanding of the pathophysiology, diagnosis, and management of cholestatic liver disease.
Collapse
Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria
| | | |
Collapse
|
|
29
|
Pereira SP, O'Donohue J, Moniz C, Phillips MG, Abraha H, Buxton-Thomas M, Williams R. Transdermal hormone replacement therapy improves vertebral bone density in primary biliary cirrhosis: results of a 1-year controlled trial. Aliment Pharmacol Ther 2004; 19:563-70. [PMID: 14987325 DOI: 10.1111/j.1365-2036.2004.01890.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Retrospective studies have suggested that hormone replacement therapy may reduce the rate of bone loss in primary biliary cirrhosis, but no controlled data are available. METHODS Forty-two post-menopausal women with primary biliary cirrhosis were treated with calcium and vitamin D, either alone (n = 21) or together with transdermal hormone replacement therapy (n = 21). Bone densitometry was performed at baseline and at 1 year, and serum and urinary markers of bone turnover were measured at three-monthly intervals. RESULTS At entry, 17 patients (40%) had spinal or femoral osteopenia (T score - 1 to - 2.5) and nine (21%) had osteoporosis (T < - 2.5). In those given hormone replacement therapy, there was a significant decrease in the mean urinary deoxypyridinoline :creatinine ratios at 3 months (7.8 vs. 6.1 nm/mm creatinine for no hormone replacement therapy vs. hormone replacement therapy; P = 0.04) and a 48% reduction in urinary calcium excretion at 1 year (0.66 vs. 0.32 mm/mm creatinine; P = 0.01). Repeat bone densitometry at 1 year revealed a 2.25% increase in the hormone replacement therapy group (P = 0.02), compared with a non-significant 0.87% decrease in L2-L4 bone mineral density in those not given hormone replacement therapy. Both treatment regimens were well tolerated, with no increase in cholestasis. CONCLUSIONS Compared with calcium and vitamin D alone, supplemental treatment with transdermal hormone replacement therapy for 1 year improved the vertebral bone density and urinary markers of bone turnover in post-menopausal women with primary biliary cirrhosis.
Collapse
Affiliation(s)
- S P Pereira
- Institute of Liver Studies, King's College Hospital, London, UK.
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic disease where there is progressive, granulomatous destruction of the middle-sized bile ducts. The disease affects mainly middle-aged women. The association with other autoimmune diseases and the widespread disturbance of the humoral and cellular immune systems has led to the inclusion of PBC as an autoimmune disease. However, there are several lines of evidence that suggest that both host and environmental factors are implicated in triggering the disease. Without a clear aetiology, it is difficult to find a logical approach to treatment. Well constructed clinical trials are difficult to run because of the variable and long natural history of the disease; and suitable endpoints are difficult to define and validated surrogate endpoints have not been defined. The only drug licensed for use is the bile acid, ursodeoxycholic acid. This drug is associated with significant biochemical improvement and improvement in the immunological disturbances (including a reduction in the titre of the diagnostic autoantibody, antimitochondrial antibody), but the effect on survival and histological progression is still controversial. There is little effect on symptoms. Nonetheless, its safety and lack of toxicity have meant that it has become the drug of choice and most studies now assess the effect of additional treatments. Many other agents have been studied. There is some evidence, from prospective, controlled studies, for a beneficial effect of azathioprine and ciclosporin (cyclosporine); evidence for a beneficial effect of corticosteroids and of mycophenolate is limited and there is little firm evidence for a beneficial effect of methotrexate, penicillamine, thalidomide or colchicine. Other treatments being evaluated include fibric acid derivatives (fibrates), NSAIDs and leukotriene antagonists. Liver transplantation remains the only option for end-stage disease but recurrence of disease may be found in the graft. Experimental therapies include antiretroviral therapy. Symptomatic treatment is required for pruritus and the mainstays are the bile acid binding agents such as colestyramine. For those who are intolerant of the drug or where it is ineffective, rifampicin and naltrexone may be effective. There is no effective treatment for the associated lethargy.
Collapse
Affiliation(s)
- Ye H Oo
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
| | | |
Collapse
|