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Boulos M, Mousa RS, Jeries N, Simaan E, Alam K, Bulus B, Assy N. Hidden in the Fat: Unpacking the Metabolic Tango Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Syndrome. Int J Mol Sci 2025; 26:3448. [PMID: 40244398 PMCID: PMC11989262 DOI: 10.3390/ijms26073448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/25/2025] [Accepted: 03/30/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.
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Affiliation(s)
- Mariana Boulos
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Rabia S. Mousa
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nizar Jeries
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Elias Simaan
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Klode Alam
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Bulus Bulus
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nimer Assy
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
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Shirinezhad A, Eshlaghi FM, Salabat D, Azarboo A, Ardakani ZF, Esmaeili S, Hoveidaei AH, Ghaseminejad-Raeini A. Prevalent osteoporosis and fracture risk in patients with hepatic cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:115. [PMID: 40000980 PMCID: PMC11853567 DOI: 10.1186/s12876-025-03720-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/20/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Hepatic liver cirrhosis can lead to significant systemic complications, including the deterioration of bone health. The resulting bone complications can contribute to a decreased quality of life and increased healthcare burden. This study aimed to systematically review and analyze the risk of osteoporosis, fracture, and changes in bone mineral density (BMD) among patients with hepatic cirrhosis compared to non-cirrhotic healthy controls. METHODS Adhering to PRISMA guidelines, studies were sourced from MEDLINE/PubMed, Scopus, Web of Science, and Embase up to July 2024, including observational studies that assessed osteoporosis, fracture, and BMD in cirrhotic versus non-cirrhotic patients. Meta-analyses were performed by calculating odds ratios (OR) and standardized mean differences (SMD) of outcomes. Sensitivity analyses and meta-regression were also conducted to explore the robustness and sources of heterogeneity. RESULTS The analysis included 21 studies with 76,521 cirrhotic and 695,330 control patients. Cirrhotic patients demonstrated significantly higher odds of osteoporosis (OR = 1.93 [1.84 to 2.03]). Fracture was notably elevated, with cirrhotic patients showing an OR of 2.30 [1.66 to 3.18]. Reductions in BMD were observed in both the lumbar spine (SMD = -0.57[-0.79 to -0.35]) and femoral neck (SMD = -0.41 [-0.71 to -0.12]). Sensitivity analyses confirmed these findings, and meta-regression highlighted that male prevalence impacted these associations in various ways. CONCLUSIONS Patients with hepatic cirrhosis are at heightened risk for osteoporosis and fractures, underlining the need for proactive screening and preventive strategies. Integrating cirrhosis into current fracture-risk models could enhance the assessment and management of bone health in these patients.
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Affiliation(s)
| | | | - Dorsa Salabat
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Azarboo
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sina Esmaeili
- Sina University Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Human Hoveidaei
- Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Ghaseminejad-Raeini
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- School of Medicine, Tehran University of Medical Sciences, Tehran Province, District 6, Pour Sina St, P94V+8MF, Tehran, Iran.
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Niwa T, Saeki C, Saito M, Oikawa T, Kamioka H, Kanai T, Ueda K, Nakano M, Torisu Y, Saruta M, Tsubota A. Impact of frailty and prevalent fractures on the long-term prognosis of patients with cirrhosis: a retrospective study. Sci Rep 2025; 15:186. [PMID: 39747234 PMCID: PMC11696115 DOI: 10.1038/s41598-024-83984-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 12/18/2024] [Indexed: 01/04/2025] Open
Abstract
Frailty and fractures are closely associated with adverse clinical outcomes. This retrospective study investigated the prognostic impact of frailty, prevalent fractures, and the coexistence of both in patients with cirrhosis. Frailty was defined according to the Fried frailty phenotype criteria: weight loss, weakness, exhaustion, slowness, and low physical activity. Prevalent fractures were assessed using questionnaires and lateral thoracolumbar spine radiographs. Cumulative survival rates were compared between the frailty and non-frailty groups, fracture and non-fracture groups, and all four groups stratified by the presence or absence of frailty and/or prevalent fractures. Among 189 patients with cirrhosis, 70 (37.0%) and 74 (39.2%) had frailty and prevalent fractures, respectively. The median observation period was 64.4 (38.6-71.7) months, during which 50 (26.5%) liver disease-related deaths occurred. Multivariate analysis identified frailty and prevalent fractures as significant independent prognostic factors in the overall cohort (p < 0.001 and p = 0.003, respectively). The cumulative survival rates were lower in the frailty or fracture groups than in the non-frailty or non-fracture groups, respectively, in the overall cohort and in patients with compensated and decompensated cirrhosis. Patients with both frailty and prevalent fractures showed the lowest cumulative survival rates, whereas those without these comorbidities showed the highest cumulative survival rates among the four stratified groups. Frailty and prevalent fractures were independently associated with mortality in patients with cirrhosis. Additionally, the coexistence of both comorbidities worsened the prognosis.
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Affiliation(s)
- Takashi Niwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
- Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan.
| | - Mitsuru Saito
- Department of Orthopedic Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroshi Kamioka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomoya Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Kaoru Ueda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Akihito Tsubota
- Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan.
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Saeki C, Saito M, Tsubota A. Association of chronic liver disease with bone diseases and muscle weakness. J Bone Miner Metab 2024; 42:399-412. [PMID: 38302761 DOI: 10.1007/s00774-023-01488-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/16/2023] [Indexed: 02/03/2024]
Abstract
The liver is a vital organ involved in nutrient metabolism, hormone regulation, immunity, cytokine production, and gut homeostasis. Impairment in liver function can result in malnutrition, chronic inflammation, decreased anabolic hormone levels, and dysbiosis. These conditions eventually cause an imbalance in osteoblast and osteoclast activities, resulting in bone loss. Osteoporosis is a frequent complication of chronic liver disease (CLD) that adversely affects quality of life and increases early mortality. Sarcopenia is another common complication of CLD characterized by progressive loss of skeletal muscle mass and function. Assessment criteria for sarcopenia specific to liver disease have been established, and sarcopenia has been reported to be associated with an increase in the risk of liver disease-related events and mortality in patients with CLD. Owing to their similar risk factors and underlying pathophysiological mechanisms, osteoporosis and sarcopenia often coexist (termed osteosarcopenia), progress in parallel, and further exacerbate the conditions mentioned above. Therefore, comprehensive management of these musculoskeletal disorders is imperative. This review summarizes the clinical implications and characteristics of osteoporosis, extending to sarcopenia and osteosarcopenia, in patients with CLD caused by different etiologies.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Mitsuru Saito
- Department of Orthopedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Akihito Tsubota
- Project Research Units, Research Center for Medical Science, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
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Quiroz-Aldave JE, Gamarra-Osorio ER, Durand-Vásquez MDC, Rafael-Robles LDP, Gonzáles-Yovera JG, Quispe-Flores MA, Concepción-Urteaga LA, Román-González A, Paz-Ibarra J, Concepción-Zavaleta MJ. From liver to hormones: The endocrine consequences of cirrhosis. World J Gastroenterol 2024; 30:1073-1095. [PMID: 38577191 PMCID: PMC10989500 DOI: 10.3748/wjg.v30.i9.1073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 01/02/2024] [Accepted: 02/06/2024] [Indexed: 03/06/2024] Open
Abstract
Hepatocrinology explores the intricate relationship between liver function and the endocrine system. Chronic liver diseases such as liver cirrhosis can cause endocrine disorders due to toxin accumulation and protein synthesis disruption. Despite its importance, assessing endocrine issues in cirrhotic patients is frequently neglected. This article provides a comprehensive review of the epidemiology, pathophysiology, diagnosis, and treatment of endocrine disturbances in liver cirrhosis. The review was conducted using the PubMed/Medline, EMBASE, and Scielo databases, encompassing 172 articles. Liver cirrhosis is associated with endocrine disturbances, including diabetes, hypoglycemia, sarcopenia, thyroid dysfunction, hypogonadotropic hypogonadism, bone disease, adrenal insufficiency, growth hormone dysfunction, and secondary hyperaldosteronism. The optimal tools for diagnosing diabetes and detecting hypoglycemia are the oral glucose tolerance test and continuous glucose monitoring system, respectively. Sarcopenia can be assessed through imaging and functional tests, while other endocrine disorders are evaluated using hormonal assays and imaging studies. Treatment options include metformin, glucagon-like peptide-1 analogs, sodium-glucose co-transporter-2 inhibitors, and insulin, which are effective and safe for diabetes control. Established standards are followed for managing hypoglycemia, and hormone replacement therapy is often necessary for other endocrine dysfunctions. Liver transplantation can address some of these problems.
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Affiliation(s)
| | | | | | | | | | | | | | - Alejandro Román-González
- Department of Endocrinology, Hospital Universitario de San Vicente Fundación, Medellin 050010, Colombia
- Internal Medicine, Universidad de Antioquia, Medellín 050010, Colombia
| | - José Paz-Ibarra
- School of Medicine, Universidad Nacional Mayor de San Marcos, Lima 15081, Peru
- Department of Endocrinology, Hospital Nacional Edgardo Rebagliati Martins, Lima 15072, Peru
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Thomson M, Scott A, Trost S, Lake J, Lim N. Low screening rates and high prevalence of osteoporosis in cirrhosis: A real-world retrospective analysis. Aliment Pharmacol Ther 2024; 59:535-546. [PMID: 38059360 DOI: 10.1111/apt.17823] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/23/2023] [Accepted: 11/21/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Patients with cirrhosis are at increased risk for osteoporosis, and those who suffer a fracture are at high risk for mortality. Despite this, osteoporosis is often overlooked and undertreated. This study aimed to evaluate osteoporosis screening, management, and adverse osteoporosis medication events in patients with cirrhosis. METHODS We performed a retrospective chart review of adult outpatients with compensated and decompensated cirrhosis seen in single health system over a 6-year period. Patient demographics, liver and bone health comorbidities, DEXA scan results, and medications were abstracted. RESULTS In total, 5398 patients met criteria. The cohort was predominately white (79.1%) and older (age 59). 44.4% were female. 64.6% had decompensated cirrhosis. Median MELD-Na score was 12.8. 23.5% had a DEXA scan ordered, approximately 50% completed this test. Patients who were older, female, white, with more severe liver disease, and other osteoporosis risk factors were more likely to have a DEXA scan ordered. 48.5% of patients had osteopenia and 30.2% had osteoporosis on DEXA scan. Only 22.6% of patients with osteoporosis received treatment, most commonly oral bisphosphonates. Oral bisphosphonate prescription was not associated with variceal bleeding (8.4% without vs. 4.8% with, p = 0.487). CONCLUSION A minority of patients with cirrhosis were screened for osteoporosis. The majority screened had osteopenia or osteoporosis on DEXA scan. Less than a quarter of patients with osteoporosis were started on treatment. Real-world experience of oral bisphosphonate use did not reveal higher rates of gastrointestinal bleeding. There is room for improvement in all aspects of bone health care in cirrhosis.
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Affiliation(s)
- Mary Thomson
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Adam Scott
- University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Suzanne Trost
- Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jack Lake
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Nicholas Lim
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
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DiLeo DA, Gidener T, Aytaman A. Chronic Liver Disease in the Older Patient-Evaluation and Management. Curr Gastroenterol Rep 2023; 25:390-400. [PMID: 37991713 DOI: 10.1007/s11894-023-00908-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2023] [Indexed: 11/23/2023]
Abstract
PURPOSE OF REVIEW As our population ages, the number of elderly patients with advanced chronic liver disease (ACLD) will increase. In this review we explore risk factors for liver injury, noninvasive assessment of liver disease, complications of cirrhosis, and management of frailty and sarcopenia in the older patient with ACLD. RECENT FINDINGS Multiple guidelines regarding ACLD have been updated over the past few years. New cutoffs for FIB-4 and NAFLD (MASLD - Metabolic Dysfunction Associated Steatotic Liver Disease) fibrosis scores for elderly patients are being validated. Older patients with MASLD benefit from caloric restriction, exercise programs, and GLP-1 agonists. Patients with ACLD need to be screened for alcohol use disorder with modified scoring systems, and if positive, benefit from referral to chemical dependency programs. Carvedilol and diuretics may safely be used in the elderly for portal hypertension and ascites, respectively, with careful monitoring. Malnutrition, frailty, sarcopenia, and bone mineral disease are common in older patients with ACLD, and early intervention may improve outcomes. Early identification of ACLD in elderly patients allows us to manage risk factors for liver injury, screen for complications, and implement lifestyle and pharmacological therapy to reduce decompensation and death. Future studies may clarify the role of noninvasive imaging in assessing liver fibrosis in the elderly and optimal interventions for nutrition, frailty, sarcopenia, bone health in addition to reevaluation of antibiotic prophylaxis for liver conditions with rising antibiotic resistance.
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Affiliation(s)
- Daniel Anthony DiLeo
- Department of Gastroenterology, Brooklyn Campus of the Veterans Affairs New York Harbor Healthcare System, 800 Poly Pl, Brooklyn, NY, 11209, USA.
| | - Tolga Gidener
- Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, 11203, USA
| | - Ayse Aytaman
- Department of Gastroenterology, Brooklyn Campus of the Veterans Affairs New York Harbor Healthcare System, 800 Poly Pl, Brooklyn, NY, 11209, USA
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Sarici KB, Akbulut S, Uremis MM, Garzali IU, Kucukakcali Z, Koc C, Turkoz Y, Usta S, Baskiran A, Aloun A, Yilmaz S. Evaluation of Bone Mineral Metabolism After Liver Transplantation by Bone Mineral Densitometry and Biochemical Markers. Transplant Proc 2023; 55:1239-1244. [PMID: 37127514 DOI: 10.1016/j.transproceed.2023.03.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 05/03/2023]
Abstract
AIM This study aimed to evaluate the course of bone and mineral metabolism after liver transplantation (LT) in patients with chronic liver disease. METHODS One hundred four patients who had undergone LT and had a minimum of 6 months of follow-up after LT were included in this prospective cohort study. The following parameters were evaluated for each patient: preoperative and postoperative (postoperative day [POD]30, POD90, POD180) osteocalcin, bone-specific alkaline phosphatase (BALP), type 1 collagen, beta-C-terminal end telopeptide (β-CTx), vitamin D, parathyroid hormone (PTH), ALP, calcium, phosphate, sedimentation, and bone mineral densitometer scores (L2, L4, L total, and F total). The parameters were compared in terms of sex, presence of liver tumor (hepatocellular carcinoma [HCC; n = 19] vs non-HCC [n = 85]), and presence of autoimmune liver disease (autoimmune liver disease [ALD; n = 8] vs non-ALD [n = 96]). RESULTS The median age of the patients (n = 81 men and n = 23 women) was 52 years (95% CI, 50-56). There was a significant change in the defined time intervals in parameters such as osteocalcin (P < .001), BALP (P < .001), β-CTx (P < .001), vitamin D (P < .001), PTH (P < .001), ALP (P = .001), calcium (P < .001), phosphate (P = .001), L2 (P = .038), L total (P = .026), and F total (P < .001) scores. There was a significant difference in POD90 ALP (P = .033), POD180 calcium (P = .011), POD180 phosphate (P = .011), preoperative sedimentation (P = .032), and POD180 F total (P = .013) scores between both sexes. There was a significant difference in POD180 osteocalcin (P = .023), POD180 β-CTx (P = .017), and preOP calcium (P = .003) among the HCC and non-HCC groups. Furthermore, we found significant differences in preoperative ALP (P = .008), preoperative sedimentation (P = .019), POD90 (P = .037) and POD180 L2 (P = .005) scores, preoperative (P = .049) and POD180 L4 (P = .017), and POD180 L total (P = .010) and F total (P = .022) scores between the patients with and without ALD. CONCLUSION This study shows that the bone and mineral metabolism of the LT recipients was negatively affected after LT. In addition, we showed that bone and mineral metabolism was more prominent in patients with HCC, and bone mineral density scores were higher in patients with ALD.
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Affiliation(s)
- Kemal Baris Sarici
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Sami Akbulut
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey; Department Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya, Turkey.
| | - Muhammed Mehdi Uremis
- Department of Medical Biochemistry, Inonu University Faculty of Medicine, Malatya, Turkey
| | | | - Zeynep Kucukakcali
- Department Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Cemalettin Koc
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Yusuf Turkoz
- Department of Medical Biochemistry, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Sertac Usta
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Adil Baskiran
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
| | - Ali Aloun
- King Hussein Medical Center, Royal Medical Services, Amman, Jordan
| | - Sezai Yilmaz
- Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey
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Musio A, Perazza F, Leoni L, Stefanini B, Dajti E, Menozzi R, Petroni ML, Colecchia A, Ravaioli F. Osteosarcopenia in NAFLD/MAFLD: An Underappreciated Clinical Problem in Chronic Liver Disease. Int J Mol Sci 2023; 24:7517. [PMID: 37108675 PMCID: PMC10139188 DOI: 10.3390/ijms24087517] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/07/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
Chronic liver disease (CLD), including non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), affects a significant portion of the population worldwide. NAFLD is characterised by fat accumulation in the liver, while NASH is associated with inflammation and liver damage. Osteosarcopenia, which combines muscle and bone mass loss, is an emerging clinical problem in chronic liver disease that is often underappreciated. The reductions in muscle and bone mass share several common pathophysiological pathways; insulin resistance and chronic systemic inflammation are the most crucial predisposing factors and are related to the presence and gravity of NAFLD and to the worsening of the outcome of liver disease. This article explores the relationship between osteosarcopenia and NAFLD/MAFLD, focusing on the diagnosis, prevention and treatment of this condition in patients with CLD.
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Affiliation(s)
- Alessandra Musio
- Department of Medical and Surgical Sciences, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (F.P.); (L.L.); (B.S.); (E.D.); (M.L.P.)
| | - Federica Perazza
- Department of Medical and Surgical Sciences, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (F.P.); (L.L.); (B.S.); (E.D.); (M.L.P.)
| | - Laura Leoni
- Department of Medical and Surgical Sciences, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (F.P.); (L.L.); (B.S.); (E.D.); (M.L.P.)
- Division of Metabolic Diseases and Clinical Nutrition, Department of Specialistic Medicines, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy;
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (F.P.); (L.L.); (B.S.); (E.D.); (M.L.P.)
| | - Elton Dajti
- Department of Medical and Surgical Sciences, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (F.P.); (L.L.); (B.S.); (E.D.); (M.L.P.)
| | - Renata Menozzi
- Division of Metabolic Diseases and Clinical Nutrition, Department of Specialistic Medicines, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy;
| | - Maria Letizia Petroni
- Department of Medical and Surgical Sciences, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (F.P.); (L.L.); (B.S.); (E.D.); (M.L.P.)
| | - Antonio Colecchia
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy;
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (F.P.); (L.L.); (B.S.); (E.D.); (M.L.P.)
- Gastroenterology Unit, Department of Medical Specialties, University Hospital of Modena, University of Modena & Reggio Emilia, 41121 Modena, Italy;
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Tenório JR, Bueno MV, Franco JB, Peres MPSDM, Moratto BMN, Munhoz L, Arita ES, Ortega KL. Assessment of mandibular cortical index in patients with hepatic cirrhosis: A case-control study. SPECIAL CARE IN DENTISTRY 2023; 43:119-124. [PMID: 35709388 DOI: 10.1111/scd.12747] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/18/2022] [Accepted: 05/28/2022] [Indexed: 11/26/2022]
Abstract
AIMS To assess the presence of alterations suggestive of reduced bone mineral density (BMD) by using mandibular cortical index (MCI) in panoramic radiographs of cirrhotic individuals and to evaluate their relationship with other characteristics of hepatic cirrhosis (HC). METHODS AND RESULTS This is an observational case-control study assessing the medical records of 165 cirrhotic patients matched by sex and age with healthy individuals. MELD (model of end stage liver disease) score, etiology, complications, comorbidities, and serum levels of vitamin D were collected. MCI was used to obtain BMD. Binary logistic regression was used to test associations and the risk estimates were expressed in odds ratio. Most of the sample consisted of men (73.93%) with median age of 56 years old. In the study group, the mean value of MELD was 16.5 and hepatitis C was the main etiology of HC (33.9%). Cirrhotic individuals are 3.99 times more likely to present alterations suggestive of reduced BMD (p < .01). There was no statistical significance in the association of MCI with levels of vitamin D, comorbidities, etiology or cirrhosis complications. CONCLUSIONS MCI suggestive of reduced BMD is more likely to be identified in panoramic radiographs of cirrhotic individuals than of healthy ones.
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Affiliation(s)
- Jefferson Rocha Tenório
- Special Care Dentistry Centre (CAPE), Department of Stomatology of the University of São Paulo, School of Dentistry, São Paulo, SP, Brazil
- Department of Pathology and Oral Diagnosis of the Federal University of Rio de Janeiro, School of Dentistry, Rio de Janeiro, RJ, Brazil
| | - Marcus Vinícius Bueno
- Special Care Dentistry Centre (CAPE), Department of Stomatology of the University of São Paulo, School of Dentistry, São Paulo, SP, Brazil
| | - Juliana Bertoldi Franco
- Division of Dentistry of the Clinics Hospital of the University of São Paulo School of Medicine, São Paulo, SP, Brazil
| | | | - Beatriz Mota Nunes Moratto
- Special Care Dentistry Centre (CAPE), Department of Stomatology of the University of São Paulo, School of Dentistry, São Paulo, SP, Brazil
| | - Luciana Munhoz
- Division of Oral Radiology, Department of Stomatology of the University of São Paulo, School of Dentistry, São Paulo, SP, Brazil
| | - Emiko Saito Arita
- Division of Oral Radiology, Department of Stomatology of the University of São Paulo, School of Dentistry, São Paulo, SP, Brazil
| | - Karem L Ortega
- Special Care Dentistry Centre (CAPE), Department of Stomatology of the University of São Paulo, School of Dentistry, São Paulo, SP, Brazil
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Muacevic A, Adler JR, Puli SR. Prevalence of Osteoporosis in Cirrhosis: A Systematic Review and Meta-Analysis. Cureus 2023; 15:e33721. [PMID: 36788896 PMCID: PMC9922208 DOI: 10.7759/cureus.33721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2023] [Indexed: 01/14/2023] Open
Abstract
The prevalence of osteoporosis in individuals with cirrhosis varies based on the diagnostic approach and etiology of the underlying liver disease. This systematic review aims to evaluate the prevalence of osteoporosis in individuals with cirrhosis. Electronic databases were searched for studies reporting the prevalence of osteoporosis among patients with cirrhosis. The primary outcome was the presence of osteoporosis, as determined by a dual-energy x-ray absorptiometry (DEXA) scan. Secondary outcomes were levels of biochemical markers of bone metabolism, including calcium, vitamin D, phosphorus, and parathormone (PTH) levels. A cohort of 836 patients from 10 studies was included in the final analysis. The pooled rate of osteoporosis was 14.80% (95% CI: 14.19-15.49). Pooled levels of biochemical markers of bone metabolism were as follows: calcium 9.09 mg/dL (95% CI: 8.73-9.45), 25-hydroxyvitamin D (25-OH vitamin D) 15.41 ng/mL (95% CI: 14.79-16.03), phosphorus 15.41 mg/dL (95% CI: 2.99-3.51), and PTH 26.58 pg/mL (95% CI: 25.45-27.71). Pooled levels of liver biochemistries were: bilirubin 3.04 mg/dL (95% CI: 2.84-3.25), aspartate aminotransferase (AST) 65.35 U/L (95% CI: 61.39-69.31), alanine aminotransferase (ALT) 50.17 U/L (95% CI: 46.18-54.10), alkaline phosphatase 133.31 U/L (95% CI: 124.89-141.73), and albumin 3.25 g/dL (95% CI: 3.05-3.45). Cirrhosis appears to be associated with an increased risk for osteoporosis, with a pooled prevalence of 15%. This can include men and individuals younger than 50 years of age, a cohort not typically considered to be at an increased risk of osteoporosis. Levels of 25-hydroxyvitamin D and insulin-like growth factor-1 (IGF-1) were also significantly low. Further studies are required to evaluate the risk of osteoporosis based on the etiology and stage of cirrhosis, especially in younger males, to incorporate this into future prediction models for fragility fractures.
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Wang J, Wu S, Zhang Y, Yang J, Hu Z. Gut microbiota and calcium balance. Front Microbiol 2022; 13:1033933. [PMID: 36713159 PMCID: PMC9881461 DOI: 10.3389/fmicb.2022.1033933] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 11/30/2022] [Indexed: 12/31/2022] Open
Abstract
Microorganisms living on the surface and inside the human body play an important role in the physiological activities of the human body. The largest microecosystem in the human body is the gut microbiome. Calcium disorders are found in many diseases. For example, patients with chronic renal insufficiency present with secondary hyperparathyroidism, which is caused by a calcium imbalance in the body. In addition, calcium dysregulation may affect lipid metabolism in the liver through the calmodulator pathway, leading to cirrhosis, etc. Currently, a considerable number of probiotics have been proven to enhance the body's absorption of calcium. This paper reviews the effects of intestinal flora and related factors such as short-chain fatty acids, estrogen, immune factors and vitamin D on calcium balance.
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Affiliation(s)
- Jiali Wang
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, BeiJing, China
| | - Shuang Wu
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yinshan Zhang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jiao Yang
- Department of Pathology, Changsha Medical School, Changsha, Hunan, China,*Correspondence: Jiao Yang,
| | - Zhongliang Hu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China,Zhongliang Hu,
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13
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Santos LAA, Lima TB, de Carvalho Nunes HR, Qi X, Romeiro FG. Two-year risedronate treatment for osteoporosis in patients with esophageal varices: a non-randomized clinical trial. Hepatol Int 2022; 16:1458-1467. [PMID: 35767173 DOI: 10.1007/s12072-022-10366-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/07/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND Bisphosphonates are the mainstay of osteoporosis treatment, but their use for patients with esophageal varices has been avoided due to the risk of esophagitis, which may cause variceal bleeding. Since most clinical trials assessing osteoporosis treatment last 2-3 years, this study aimed to evaluate a 2-year risedronate treatment for patients with esophageal varices and liver cirrhosis. METHODS The study received Institutional Review Board approval, and the sample was divided into two groups according to bone mineral density (BMD). Cirrhosis severity and endoscopic findings at baseline were similar between the groups. The intervention group had 51 patients with osteoporosis, who received oral risedronate 35 mg weekly plus calcium and vitamin D supplements. The control group had 51 patients with osteopenia, receiving only the supplements. Scheduled esophagogastroduodenoscopies and BMD measurements were carried out. RESULTS The adjusted esophagitis risk was higher in the intervention group; however, none of the subjects had digestive bleeding. Lumbar spine BMD increased in the intervention group (- 3.06 ± 0.71 to - 2.33 ± 0.90; p < 0.001) and in the control group (- 1.38 ± 0.77 to - 1.10 ± 1.05; p = 0.012). Femoral neck BMD did not change in the intervention group (- 1.64 ± 0.91 to - 1.71 ± 0.95; p = 0.220), but tended to decrease in the control group (- 1.00 ± 0.74 to - 1.09 ± 0.82; p = 0.053). CONCLUSION Oral risedronate was effective and did not cause gastrointestinal bleeding in cirrhotic patients with esophageal varices under endoscopic surveillance.
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Affiliation(s)
- Lívia Alves Amaral Santos
- Internal Medicine Department, Botucatu Medical School, Gastroenterology Division-São Paulo State University (UNESP), Rubião Júnior s/n, Botucatu, SP, CEP 18618-687, Brazil
| | - Talles Bazeia Lima
- Internal Medicine Department, Botucatu Medical School, Gastroenterology Division-São Paulo State University (UNESP), Rubião Júnior s/n, Botucatu, SP, CEP 18618-687, Brazil
| | | | - Xingshun Qi
- General Hospital of Shenyang Military Command, Liaoning, Sheng, China
| | - Fernando Gomes Romeiro
- Internal Medicine Department, Botucatu Medical School, Gastroenterology Division-São Paulo State University (UNESP), Rubião Júnior s/n, Botucatu, SP, CEP 18618-687, Brazil.
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Nath P, Anand AC. Extrahepatic Manifestations in Alcoholic Liver Disease. J Clin Exp Hepatol 2022; 12:1371-1383. [PMID: 36157144 PMCID: PMC9499846 DOI: 10.1016/j.jceh.2022.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/20/2022] [Indexed: 12/12/2022] Open
Abstract
Though liver is the most commonly affected organ in patients with chronic and excessive intake of alcohol, no organ is immune to toxic effects of alcohol and patients with alcohol-related liver disease (ALD) can suffer from a wide list of extrahepatic manifestations involving gastrointestinal tract, central and peripheral nervous systems, cardio vascular system, musculo-skeletal system, disruption of nutritional status, endocrinological abnormalities, hematological abnormalities and immune dysfunction. These extrahepatic organ involvements are usually overlooked by hepatologists and physicians who are mostly focused on managing life threatening complications of ALD. As a result, there is delayed diagnosis, delay in the initiation of appropriate treatment and late referral to other specialists. Some of these manifestations are of utmost clinical importance (e.g. delirium tremans and Wernicke's encephalopathy) because an early diagnosis and treatment can lead to full recovery while delayed or no treatment can result in death. On the other hand, several extrahepatic manifestations are of prognostic significance (such as alcoholic cardiomyopathy and malignancies) in which there is an increased risk of morbidity and mortality. Hence, a clear understanding and awareness of the extrahepatic manifestations of ALD is quintessential for proper management of these patients.
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Key Words
- ACE, Angiotensin-Converting-Enzyme
- ALD, Alcohol related Liver Disease
- AUD, Alcohol Use Disorder
- GAVE, Gastric Antral Vascular Ectasia
- GERD, Gastro-Esophageal Reflux Disease
- HCC, Hepatocellular Carcinoma
- HIV, Human Immunodeficiency Virus
- IARC, International Agency for Research on Cancer
- IL, Interleukin
- NERD, Non-Erosive Reflux Disease
- PPI, Proton Pump Inhibitors
- TNF, Tumour Necrosis Factor
- UGI, Upper Gastrointestinal
- WHO, World Health Organization
- alcohol use disorder
- alcohol withdrawal syndrome
- alcoholic cardiomyopathy
- alcoholic liver disease
- alcoholic myopathy
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Affiliation(s)
- Preetam Nath
- Department of Gastroenterology & Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, 751024, India
| | - Anil C. Anand
- Department of Gastroenterology & Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, 751024, India
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Serum Insulin-Like Growth Factor 1 Levels, Facture Risk Assessment Tool Scores and Bone Disorders in Patients with Primary Biliary Cholangitis. Diagnostics (Basel) 2022; 12:diagnostics12081957. [PMID: 36010307 PMCID: PMC9407172 DOI: 10.3390/diagnostics12081957] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/17/2022] Open
Abstract
Insulin-like growth factor 1 (IGF-1) plays an important role in bone growth and maintenance, and its decreased levels are associated with bone disorders. This study aimed to evaluate the association of serum IGF-1 levels with osteoporosis, prevalent fractures and fracture risk based on the Fracture Risk Assessment Tool (FRAX) in patients with primary biliary cholangitis (PBC). This study included 127 consecutive patients with PBC. Based on the baseline serum IGF-1 levels, the participants were classified into the low (L)-, intermediate (I)- and high (H)-IGF-1 groups. According to the FRAX score, high fracture risk was defined as a 10-year major osteoporotic fracture probability (FRAX-MOF) ≥ 20% or a 10-year hip fracture probability (FRAX-HF) ≥ 3%. The serum IGF-1 levels were positively correlated with bone mineral density, and were negatively correlated with the FRAX-MOF/FRAX-HF. The L-IGF-1 group had the highest prevalence of osteoporosis (58.1%), prevalent fracture (48.4%) and high fracture risk (71.0%). Meanwhile, the H-IGF-1 group had the lowest prevalence of osteoporosis (9.7%), prevalent fracture (12.9%) and high fracture risk (9.7%). The prevalence of these events increased stepwise with decreasing serum IGF-1 levels. The cutoff values of IGF-1 for predicting osteoporosis, prevalent fracture and high fracture risk were 61.5 ng/mL (sensitivity/specificity, 0.545/0.894), 69.5 ng/mL (0.633/0.784) and 61.5 ng/mL (0.512/0.929), respectively. Serum IGF-1 levels were associated with bone disorders and the FRAX-derived fracture risk, and may be a useful indicator for initiating therapeutic intervention to prevent the incidence of fracture in patients with PBC.
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Usefulness of the Trabecular Bone Score in Assessing the Risk of Vertebral Fractures in Patients with Cirrhosis. J Clin Med 2022; 11:jcm11061562. [PMID: 35329888 PMCID: PMC8954474 DOI: 10.3390/jcm11061562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/10/2022] [Accepted: 03/10/2022] [Indexed: 01/27/2023] Open
Abstract
The trabecular bone score (TBS), a surrogate measure of bone microarchitecture, provides complementary information to bone mineral density (BMD) in the assessment of osteoporotic fracture risk. This cross-sectional study aimed to determine whether TBS can identify patients with liver cirrhosis that are at risk of vertebral fractures. We enrolled 275 patients who completed evaluations for lumbar BMD, TBS, and vertebral fractures between November 2018 and April 2021. BMD was measured using dual-energy X-ray absorptiometry (DXA), TBS was calculated by analyzing DXA images using TBS iNsight software, and vertebral fractures were evaluated using Genant’s semi-quantitative method with lateral X-ray images. Factors associated with vertebral fractures and their correlation with the TBS were identified using regression models. Of the enrolled patients, 128 (47%) were female, the mean age was 72 years, and 62 (23%) were diagnosed with vertebral fractures. The prevalence of vertebral fractures was higher in women than in men (33% vs. 14%; p < 0.001). The unadjusted odds ratio (OR) of the vertebral fractures for one standard deviation decrease in TBS and BMD was 2.14 (95% confidence interval [CI], 1.69−2.73) and 1.55 (95% CI, 1.26−1.90), respectively. After adjusting for age, sex, and BMD, the adjusted OR of the vertebral fractures in TBS was 2.26 (95% CI, 1.52−3.35). Multivariate linear regression analysis showed that TBS was independently correlated with age (β = −0.211), body mass index (β = −0.251), and BMD (β = 0.583). TBS can help identify patients with cirrhosis at risk of vertebral fractures.
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17
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Sherwood JS, Ullal J, Kutney K, Hughan KS. Cystic fibrosis related liver disease and endocrine considerations. J Clin Transl Endocrinol 2022; 27:100283. [PMID: 35024343 PMCID: PMC8724940 DOI: 10.1016/j.jcte.2021.100283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/23/2021] [Accepted: 11/27/2021] [Indexed: 12/12/2022] Open
Abstract
Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.
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Key Words
- APRI, aspartate aminotransferase to platelet ratio
- BMI, body mass index
- CFBD, CF bone disease
- CFLD, Cystic fibrosis-liver disease
- CFRD, CF related diabetes
- CFTR, cystic fibrosis transmembrane conductance regulator
- Cirrhosis
- Cystic fibrosis liver disease
- Cystic fibrosis-related diabetes
- FFA, free fatty acids
- Fib-4, Fibrosis-4
- GH, growth hormone
- IGF-1, insulin-like growth factor-1
- Insulin resistance
- UDCA, ursodeoxycholic acid
- ULN, upper limit of normal
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Affiliation(s)
- Jordan S. Sherwood
- Department of Pediatrics, Diabetes Research Center, Division of Pediatric Endocrinology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, United States
| | - Jagdeesh Ullal
- Department of Medicine, UPMC Center for Diabetes and Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Katherine Kutney
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, United States
| | - Kara S. Hughan
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
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Effect of Vitamin D Supplementation on Vitamin D Level and Bone Mineral Density in Patients With Cirrhosis: A Randomized Clinical Trial. Am J Gastroenterol 2021; 116:2098-2104. [PMID: 33927126 DOI: 10.14309/ajg.0000000000001272] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 03/12/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION In patients with cirrhosis, highly prevalent vitamin D deficiency and low bone mineral density (BMD) increase the burden of disease, and role of vitamin D supplementation is not clear. So, our aim was to determine the effect of vitamin D supplementation on vitamin D level and BMD in patients with cirrhosis. METHODS Patients with cirrhosis (18-60 years) of any etiology were enrolled. We measured serum 25(OH)D, parathyroid hormone, thyroid-stimulating hormone, free T4, bone-specific alkaline phosphatase, insulin-like growth factor (IGF)-1, and health-related quality of life at entry and at 1 year; however, serum calcium was measured at 3-month interval. BMD was measured by dual-energy x-ray absorptiometry at lumbar spine and left hip neck at entry and after 1 year. Statistical analysis was performed according to intention-to-treat analysis. RESULTS Of 390 screened patients with cirrhosis, 164 participants (82 in each group) were randomized. There was significant increase in 25(OH)D levels in intervention group after 1 year (33.7 [24.3-45.7] ng/mL vs 23.1 [17-28.2] ng/mL; P < 0.001) when compared with placebo. The mean difference in BMD at lumbar spine and left hip neck was not significantly changed after 1 year of intervention with vitamin D between both groups. There was no significant change in both the groups in levels of calcium, thyroid-stimulating hormone, parathyroid hormone, free T4, IGF-1, and bone-specific alkaline phosphatase and quality of life. DISCUSSION Supplementation with vitamin D for 1 year improves vitamin D levels but did not result in improvement in BMD at lumbar spine and left hip neck in patients with cirrhosis.
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Walsh ME, Nerdrum M, Fahey T, Moriarty F. Factors associated with initiation of bone-health medication among older adults in primary care in Ireland. Age Ageing 2021; 50:1649-1656. [PMID: 33693466 PMCID: PMC8437061 DOI: 10.1093/ageing/afab033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Indexed: 12/13/2022] Open
Abstract
Background Adults at high risk of fragility fracture should be offered pharmacological treatment when not contraindicated, however, under-treatment is common. Objective This study aimed to investigate factors associated with bone-health medication initiation in older patients attending primary care. Design This was a retrospective cohort study. Setting The study used data from forty-four general practices in Ireland from 2011–2017. Subjects The study included adults aged ≥ 65 years who were naïve to bone-health medication for 12 months. Methods Overall fracture-risk (based on QFracture) and individual fracture-risk factors were described for patients initiated and not initiated onto medication and compared using generalised linear model regression with the Poisson distribution. Results Of 36,799 patients (51% female, mean age 75.4 (SD = 8.4)) included, 8% (n = 2,992) were observed to initiate bone-health medication during the study. One-fifth of all patients (n = 8,193) had osteoporosis or had high fracture-risk but only 21% of them (n = 1,687) initiated on medication. Female sex, older age, state-funded health cover and osteoporosis were associated with initiation. Independently of osteoporosis and co-variates, high 5-year QFracture risk for hip (IRR = 1.33 (95% CI = 1.17–1.50), P < 0.01) and all fractures (IRR = 1.30 (95% CI = 1.17–1.44), P < 0.01) were associated with medication initiation. Previous fracture, rheumatoid arthritis and corticosteroid use were associated with initiation, while liver, kidney, cardiovascular disease, diabetes and oestrogen-only hormone replacement therapy showed an inverse association. Conclusions Bone-health medication initiation is targeted at patients at higher fracture-risk but much potential under-treatment remains, particularly in those >80 years and with co-morbidities. This may reflect clinical uncertainty in older multimorbid patients, and further research should explore decision-making in preventive bone medication prescribing.
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Affiliation(s)
- Mary E Walsh
- HRB Centre for Primary Care Research, Department of General Practice, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Mari Nerdrum
- HRB Centre for Primary Care Research, Department of General Practice, Royal College of Surgeons in Ireland, Dublin, Ireland
- Graduate Entry Medicine Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Tom Fahey
- HRB Centre for Primary Care Research, Department of General Practice, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Frank Moriarty
- HRB Centre for Primary Care Research, Department of General Practice, Royal College of Surgeons in Ireland, Dublin, Ireland
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
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20
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Tenório JR, Duarte NT, Andrade NS, Bergamini ML, Mamana AC, Braz-Silva PH, Ortega KL. Assessment of bone metabolism biomarkers in serum and saliva of cirrhotic patients. Clin Oral Investig 2021; 26:1861-1868. [PMID: 34491448 DOI: 10.1007/s00784-021-04161-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 08/24/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To assess the serum and salivary levels of biomarkers related to bone metabolism in cirrhotic patients as well as the evidence of osteoporotic changes on panoramic radiographs. MATERIALS AND METHODS Thirty-eight cirrhotic patients underwent anamnesis and physical examination. Specimens of blood and saliva were collected for evaluation by using Luminex™ xMAP technology to quantify RANKL, OPG, IL-1β, IL-6 and TNF-α. Panoramic radiographs were evaluated based on the mandibular cortical index (MCI) and the resulting data were compared to the expression of biomarkers in serum and saliva. Descriptive data analysis was performed and the Mann-Whitney's test and Spearman's correlation were used. RESULTS Most of the sample consisted of males (68.4%) who had cirrhosis mostly resulting from alcoholism (28.9%). Median concentration values of RANKL (74.44 pg/mL), IL-1 β (45.91 pg/mL), IL-6 (67.69 pg/mL) and TNF-α (5.97 pg/mL) in saliva were higher than those observed in serum. In 72.7% of the panoramic radiographs, MCI was found to be suggestive of osteoporotic changes. No statistically significant correlation was observed between salivary and serum expressions of biomarkers or between biomarkers and MCI. CONCLUSION RANKL, OPG, IL-1β, IL-6 and TNF-α are expressed differently in serum and saliva and the concentration of these biomarkers is not related to MCI. CLINICAL RELEVANCE This study contributes to the study of the mechanisms of osteoporosis in cirrhotic individuals.
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Affiliation(s)
- Jefferson Rocha Tenório
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil
| | - Nathália Tuany Duarte
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil
| | - Natália Silva Andrade
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil.,Department of Dentistry, Federal University of Sergipe, Lagarto, Sergipe, Brazil
| | - Mariana Lobo Bergamini
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil
| | - Ana Carolina Mamana
- Laboratory of Virology, Institute of Tropical Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Paulo Henrique Braz-Silva
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil.,Laboratory of Virology, Institute of Tropical Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Karem L Ortega
- Department of Stomatology, University of São Paulo School of Dentistry, Av. Prof. Lineu Prestes, 2227-Butantã, São Paulo, SP, 05508-900, Brazil.
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21
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Clinical Management of Primary Biliary Cholangitis-Strategies and Evolving Trends. Clin Rev Allergy Immunol 2021; 59:175-194. [PMID: 31713023 DOI: 10.1007/s12016-019-08772-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PBC is a chronic progressive autoimmune disorder involving the destruction of intrahepatic small bile ducts, cholestasis, fibrosis, and ultimately cirrhosis if left untreated. It is largely driven by the autoimmune response, but bile acids and the intestinal microbiota are implicated in disease progression as well. The only drugs licensed for PBC are UDCA and OCA. UDCA as a first-line and OCA as a second-line therapy are safe and effective, but the lack of response in a significant portion of patients and inadequate control of symptoms such as fatigue and pruritus remain as concerns. Liver transplantation is an end-stage therapy for many patients refractory to UDCA, which gives excellent survival rates but also moderate to high recurrence rates. The limited options for FDA-approved PBC therapies necessitate the development of alternative approaches. Currently, a wide variety of experimental drugs exist targeting immunological and physiological aspects of PBC to suppress inflammation. Immunological therapies include drugs targeting immune molecules in the B cell and T cell response, and specific cytokines and chemokines implicated in inflammation. Drugs targeting bile acids are also noteworthy as bile acids can perpetuate hepatic inflammation and lead to fibrosis over time. These include FXR agonists, ASBT inhibitors, and PPAR agonists such as bezafibrate and fenofibrate. Nonetheless, many of these drugs can only delay disease progression and fail to enhance patients' quality of life. Nanomedicine shows great potential for treatment of autoimmune diseases, as it provides a new approach that focuses on tolerance induction rather than immunosuppression. Tolerogenic nanoparticles carrying immune-modifying agents can be engineered to safely and effectively target the antigen-specific immune response in autoimmune diseases. These may work well with PBC especially, given the anatomical features and immunological specificity of the disease. Nanobiological therapy is thus an area of highly promising research for future treatment of PBC.
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Yang YJ, Kim DJ. An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia. Int J Mol Sci 2021; 22:2604. [PMID: 33807573 PMCID: PMC7961345 DOI: 10.3390/ijms22052604] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.
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Affiliation(s)
- Young Joo Yang
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
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Pereira F, Azevedo R, Linhares M, Pinto J, Leitão C, Caldeira A, Tristan J, Pereira E, Sousa R, Banhudo A. Hepatic osteodystrophy in cirrhosis due to alcohol-related liver disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 113:563-569. [PMID: 33267594 DOI: 10.17235/reed.2020.7301/2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
INTRODUCTION hepatic osteodystrophy, including osteoporosis, is an abnormal bone metabolism related with chronic liver diseases. Osteoporosis is associated with an increased risk of bone fractures, with a significant impact on morbidity, mortality and healthcare costs. Nevertheless, bone disorders tend to be undervalued in cirrhosis due to alcohol-related liver disease (ALD cirrhosis). This study aimed to assess the prevalence of hepatic osteodystrophy and osteoporosis in ALD cirrhosis. METHODS a prospective observational study was performed that included patients with ALD cirrhosis, between September 2017 and December 2018. Bone mineral density was determined by dual energy X-ray absorptiometry at the lumbar spine and the femoral neck. Hepatic osteodystrophy was defined as a T-score below -1 SD and osteoporosis as a T-score below -2.5 SD. RESULTS ninety-four patients were included; 24.5 % (n = 23) had prior fragility fractures and ten patients suffered new osteoporotic fractures during the study period. Hepatic osteodystrophy was diagnosed in 79.8 % (n = 75) and osteoporosis in 21.3 % (n = 20) of cases. Patients with hepatic osteodystrophy presented significantly worse Child-Turcotte-Pugh (p < 0.05) and Model for End-Stage Liver Disease (MELD-sodium) scores (p = 0.01). According to the multivariate analysis, lower body mass index (BMI) (OR = 0.787, 95 % CI: 0.688-0.901, p = 0.001) and vitamin D deficiency (OR = 6.798, 95 % CI: 1.775-26.038, p = 0.005) were significantly and independently associated with hepatic osteodystrophy. Patients with osteoporosis also had a lower BMI (p = 0.01). Female patients and those with prior fragility fractures were more likely to suffer from osteoporosis (p < 0.05). CONCLUSION our study revealed a high prevalence of hepatic osteodystrophy and osteoporosis in patients with ALD cirrhosis (particularly in those with a lower BMI) and a concerning high rate of fragility fractures. Bone mineral density should be assessed in order to allow for an early diagnosis and the implementation of preventive measures.
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Affiliation(s)
| | | | | | - João Pinto
- Gastroenterology, Amato Lusitano Hospital, Portugal
| | - Cátia Leitão
- Gastroenterology, Amato Lusitano Hospital, Portugal
| | - Ana Caldeira
- Gastroenterology, Amato Lusitano Hospital, Portugal
| | - José Tristan
- Gastroenterology, Amato Lusitano Hospital, Portugal
| | | | - Rui Sousa
- Gastroenterology, Amato Lusitano Hospital, Portugal
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Hepatic encephalopathy increases the risk of hip fracture: a nationwide cohort study. BMC Musculoskelet Disord 2020; 21:779. [PMID: 33243187 PMCID: PMC7690159 DOI: 10.1186/s12891-020-03811-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 11/19/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Osteoporotic hip fracture is a common general health problem with a significant impact on human life because it debilitates the patients and largely decreases their quality of life. Early prevention of fractures has become essential in recent decades. This can be achieved by evaluating the related risk factors, as a reference for further intervention. This is especially useful for the vulnerable patient group with comorbidities. Hepatic encephalopathy (HE), a major complication of liver cirrhosis, may increase the rate of falls and weaken the bone. This study evaluated the correlation between hepatic encephalopathy and osteoporotic hip fracture in the aged population using a national database. METHODS This retrospective cohort study used data from Taiwan's National Health Insurance Research Database between 2000 and 2012. We included people who were older than 50 years with hepatic encephalopathy or other common chronic illnesses. Patients with and without hepatic encephalopathy were matched at a ratio of 1:4 for age, sex, and index year. The incidence and hazard ratios of osteoporotic hip fracture between the both cohorts were calculated using Cox proportional hazard regression models. RESULTS The mean age of the enrolled patients was 66.5 years. The incidence ratio of osteoporotic hip fracture in the HE group was significantly higher than that in the non-HE group (68/2496 [2.7%] vs 98/9984 [0.98%]). Patients with HE were 2.15-times more likely to develop osteoporotic hip fractures than patients without HE in the whole group. The risk ratio was also significantly higher in female and older individuals. The results were also similar in the comorbidity subgroups of hypertension, diabetes mellitus, hyperlipidemia, senile cataract, gastric ulcer, and depression. Alcohol-related illnesses seemed to not confound the results of this study. CONCLUSIONS HE is significantly associated with an increased risk of osteoporotic hip fractures, and the significance is not affected by the comorbidities in people aged more than 50 years. The cumulative risk of fracture increases with age.
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Saeki C, Saito M, Oikawa T, Nakano M, Torisu Y, Saruta M, Tsubota A. Effects of denosumab treatment in chronic liver disease patients with osteoporosis. World J Gastroenterol 2020; 26:4960-4971. [PMID: 32952342 PMCID: PMC7476181 DOI: 10.3748/wjg.v26.i33.4960] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease (CLD) patients. Denosumab has been shown to increase bone mineral density (BMD) and decrease the risk of osteoporotic fracture in the general population. However, there are few reports evaluating the efficacy of denosumab in CLD patients.
AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.
METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo. The study period for evaluating efficacy and safety was 12 mo. Changes from baseline in BMD at the lumbar spine, femoral neck, and total hip were evaluated at 12 mo of denosumab treatment. Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b (bone resorption marker), serum total procollagen type I N-terminal propeptide (bone formation maker), and plasma pentosidine (bone quality marker).
RESULTS Among the 405 CLD patients, 138 (34.1%) patients were diagnosed with osteoporosis; among these, 78 patients met the exclusion criteria and thus 60 patients were finally included in the present study. The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine, femoral neck, and total hip were +4.44%, +3.71%, and +4.03%, respectively. Denosumab significantly improved BMD, regardless of sex, patient age, and presence of liver cirrhosis. Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment (P < 0.001). Plasma pentosidine levels were also significantly lower at 12 mo of treatment (P = 0.010). No patients experienced fractures and moderate-to-severe adverse events, except for transient hypocalcemia.
CONCLUSION Denosumab treatment was safe and increased BMD, suppressed bone turnover, and improved bone quality marker levels in CLD patients with osteoporosis, irrespective of differences in baseline characteristics.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo 1058461, Japan
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Liang KH, Zhang P, Lin CL, Wang SC, Hu TH, Yeh CT, Su GL. Morphomic Signatures Derived from Computed Tomography Predict Hepatocellular Carcinoma Occurrence in Cirrhotic Patients. Dig Dis Sci 2020; 65:2130-2139. [PMID: 31677071 PMCID: PMC7195221 DOI: 10.1007/s10620-019-05915-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Computed tomography (CT) provides scans of the human body from which digitized features can be extracted. The aim of this study was to examine the role of these digital biomarkers for predicting subsequent occurrence of hepatocellular carcinoma (HCC) in cirrhotic patients. METHODS A cohort of 269 patients with cirrhosis were recruited and prospectively followed for the occurrence of HCC in Taiwan. CT scans were retrospectively retrieved and computationally processed using analytic morphomics. A predictive score was constructed using Cox regression and the generalized iterative modeling method, maximizing the log likelihood of the time to HCC development. An independent cohort of 274 patients from University of Michigan was utilized to examine the predictive validity of this score in a Western population. RESULTS Of the 27 digitized features at the 12th thoracic vertebral level, six features were significantly associated with HCC occurrence. Two digitized features (fascia eccentricity and the bone mineral density) were able to stratify patients into high- and low-risk groups with distinct cumulative incidence of HCC in both the training and validation cohorts (P = 0.015 and 0.044, respectively). When the two digitized features were tested in the Michigan cohort, only bone mineral density remained an effective predictor. CONCLUSION Digitized features derived from the CT were effective in predicting subsequent occurrence of HCC in cirrhosis patients. The bone mineral density measured on CT was an effective predictor for patients in both Taiwan and USA.
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Affiliation(s)
- Kung-Hao Liang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan,Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan,Institute of Food Safety and Health Risk Assessment, National Yang-Ming University, Taipei, Taiwan,Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
| | - Peng Zhang
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA,Morphomic Analysis Group, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Stewart C. Wang
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA,Morphomic Analysis Group, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan,Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Grace L. Su
- Morphomic Analysis Group, University of Michigan Medical School, Ann Arbor, MI, USA,Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA,VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
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Huldén E, Castedal M, Karlsson MK, Kalaitzakis E, Swärd P. Osteoporosis in cirrhotics before and after liver transplantation: relation with malnutrition and inflammatory status. Scand J Gastroenterol 2020; 55:354-361. [PMID: 32180479 DOI: 10.1080/00365521.2020.1735507] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Background: Liver cirrhosis is associated with osteoporosis and liver transplantation (LT) with increased bone loss. This study aimed to in LT candidates investigate the potential relation between bone mineral density (BMD) and BMD loss in those who undergo LT, with malnutrition, systemic inflammation, and hormonal status.Methods: We included 102 consecutively recruited cirrhotic LT candidates between May 2004 and April 2007. BMD was assessed by means of dual energy X-ray absorptiometry (DXA). Malnutrition was defined by means of anthropometry and assessment of recent weight loss. In 75/102 patients, serum-thyroid stimulating hormone (TSH), free triiodthyronine (T3) and free thyroxine (T4) and growth hormone (GH), cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor (TNF)-α was assessed. Overall 57/102 patients received a LT and 47/102 were followed for one year post-LT. At follow-up, nutritional status and BMD were assessed in all patients (n = 47) while 34/47 had available blood samples for analysis.Results: Forty (40%) LT- candidates had osteopenia or osteoporosis and 34 (38%) were malnourished. Malnutrition was associated with osteopenia/osteoporosis (odds ratio: 3.5, 95% CI 1.4, 9.9). Hip BMD Z-score decreased -0.25 (95% CI -0.41, -0.09) from baseline to one year post-LT. High baseline TNF-α correlated with a more marked decline in BMD (Partial correlation (r) = -0.47, p < .05) as did high baseline cortisol levels (r = -0.49, p < .05).Conclusion: Malnutrition in liver cirrhosis seems to be associated with osteopenia/osteoporosis, and systemic inflammation (higher TNF-α) and systemic stress (higher cortisol) to bone loss in patients who undergo LT.
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Affiliation(s)
- Ellen Huldén
- Department of Orthopaedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden
| | - Maria Castedal
- The Transplant Institute, Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Magnus K Karlsson
- Department of Orthopaedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden
| | - Evangelos Kalaitzakis
- Departement of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Copenhagen University Hospital/Herlev, University of Copenhagen, Copenhagen, Denmark.,University Hospital of Heraklion, University of Crete, Heraklion, Greece
| | - Per Swärd
- Department of Orthopaedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden
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28
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Saeki C, Takano K, Oikawa T, Aoki Y, Kanai T, Takakura K, Nakano M, Torisu Y, Sasaki N, Abo M, Matsuura T, Tsubota A, Saruta M. Comparative assessment of sarcopenia using the JSH, AWGS, and EWGSOP2 criteria and the relationship between sarcopenia, osteoporosis, and osteosarcopenia in patients with liver cirrhosis. BMC Musculoskelet Disord 2019; 20:615. [PMID: 31878909 PMCID: PMC6933666 DOI: 10.1186/s12891-019-2983-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 12/02/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sarcopenia and osteoporosis reduce life quality and worsen prognosis in patients with liver cirrhosis (LC). When these two complications coexist, a diagnosis of osteosarcopenia is made. We aimed to investigate the actual situations of sarcopenia, osteoporosis, osteosarcopenia, and vertebral fracture, and to clarify the relationship among these events in patients with LC. METHODS We describe a cross-sectional study of 142 patients with LC. Sarcopenia was defined according to the Japan Society of Hepatology (JSH) criteria, Asian Working Group for Sarcopenia (AWGS) criteria, and European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. The skeletal muscle mass index (SMI) and handgrip strength were assessed using bioelectrical impedance analysis and a digital grip strength dynamometer, respectively. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry, and vertebral fracture was evaluated using spinal lateral X-rays. The severity of LC was assessed using the Child-Pugh classification. RESULTS Among the 142 patients, the prevalence of sarcopenia was 33.8% (48/142) according to the JSH and AWGS criteria and 28.2% (40/142) according to the EWGSOP2 criteria. The number of patients with osteoporosis, osteosarcopenia, and vertebral fracture was 49 (34.5%), 31 (21.8%), and 41 (28.9%), respectively. Multivariate analysis revealed a close association between sarcopenia and osteoporosis. Osteoporosis was independently associated with sarcopenia [odds ratio (OR) = 3.923, P = 0.010]. Conversely, sarcopenia was independently associated with osteoporosis (OR = 5.722, P < 0.001). Vertebral fracture occurred most frequently in patients with osteosarcopenia (19/31; 61.3%) and least frequently in those without both sarcopenia and osteoporosis (12/76; 15.8%). The SMI and handgrip strength values were significantly correlated with the BMD of the lumbar spine (r = 0.55 and 0.51, respectively; P < 0.001 for both), femoral neck, (r = 0.67 and 0.62, respectively; P < 0.001 for both), and total hip (r = 0.67 and 0.61, respectively; P < 0.001 for both). CONCLUSIONS Sarcopenia, osteoporosis, osteosarcopenia, and vertebral fracture were highly prevalent and closely associated with one another in patients with LC. Specifically, patients with osteosarcopenia had the highest risk of vertebral fractures. Early diagnosis of these complications is essential for treatment intervention.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan. .,Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan.
| | - Keiko Takano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Yuma Aoki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.,Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Tomoya Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.,Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.,Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.,Division of Gastroenterology, Department of Internal Medicine, Fuji City General Hospital, Shizuoka, Japan
| | - Nobuyuki Sasaki
- Department of Rehabilitation Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Masahiro Abo
- Department of Rehabilitation Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomokazu Matsuura
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan.
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
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Lima TB, Santos LAA, Nunes HRDC, Silva GF, Caramori CA, Qi X, Romeiro FG. Safety and efficacy of risedronate for patients with esophageal varices and liver cirrhosis: a non-randomized clinical trial. Sci Rep 2019; 9:18958. [PMID: 31831865 PMCID: PMC6908659 DOI: 10.1038/s41598-019-55603-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023] Open
Abstract
Despite the high prevalence of osteoporosis in liver cirrhosis, the indication of bisphosphonates for patients with esophageal varices has been avoided due to risk of digestive mucosal damage. Therefore, this study aimed to evaluate the safety profile of risedronate treatment for patients with osteoporosis, liver cirrhosis and esophageal varices with low risk of bleeding. A total of 120 patients were allocated into two groups according to their bone mineral density measured by dual-energy X-ray absorptiometry. In the intervention group, 57 subjects with osteoporosis received oral risedronate at 35 mg weekly plus daily calcium and vitamin D supplementation. In the control group, 63 subjects with osteopenia received only calcium and vitamin D. The groups received the treatment for one year and underwent surveillance endoscopies at six and 12 months, as well as a control dual-energy X-ray absorptiometry after a 12-month follow-up. The study received Institutional Review Board approval. The groups had not only comparable Model for End-stage Liver Disease score and esophageal varices degree, but also similar incidence of digestive adverse effects. A significant improvement was achieved in the intervention group in the lumbar spine T score (p < 0.001). The results suggest that risedronate may be safely used in liver cirrhosis and esophageal varices with low bleeding risk under endoscopic surveillance, thus allowing bone mass recovery.
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Affiliation(s)
- Talles Bazeia Lima
- Internal Medicine Department, Gastroenterology Division - São Paulo State University (UNESP), Botucatu Medical School, São Paulo, Brazil
| | - Lívia Alves Amaral Santos
- Internal Medicine Department, Gastroenterology Division - São Paulo State University (UNESP), Botucatu Medical School, São Paulo, Brazil
| | | | - Giovanni Faria Silva
- Internal Medicine Department, Gastroenterology Division - São Paulo State University (UNESP), Botucatu Medical School, São Paulo, Brazil
| | - Carlos Antonio Caramori
- Internal Medicine Department, Gastroenterology Division - São Paulo State University (UNESP), Botucatu Medical School, São Paulo, Brazil
| | - Xingshun Qi
- General Hospital of Shenyang Military Command, Liaoning, Sheng, China
| | - Fernando Gomes Romeiro
- Internal Medicine Department, Gastroenterology Division - São Paulo State University (UNESP), Botucatu Medical School, São Paulo, Brazil.
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Jeong HM, Kim DJ. Bone Diseases in Patients with Chronic Liver Disease. Int J Mol Sci 2019; 20:4270. [PMID: 31480433 PMCID: PMC6747370 DOI: 10.3390/ijms20174270] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 08/25/2019] [Accepted: 08/28/2019] [Indexed: 02/07/2023] Open
Abstract
Osteoporosis is a frequently observed complication in patients with chronic liver disease, particularly liver cirrhosis and cholestatic liver diseases. In addition, osteoporosis is critical in patients receiving a liver transplant. Nevertheless, few studies have evaluated bone diseases in patients with more frequently observed chronic liver disease, such as chronic viral hepatitis, nonalcoholic fatty liver disease and alcoholic liver disease. Osteoporosis is a disease caused by an imbalance in the activities of osteoblasts and osteoclasts. Over the last few decades, many advances have improved our knowledge of the pathogenesis of osteoporosis. Importantly, activated immune cells affect the progression of osteoporosis, and chronic inflammation may exert an additional effect on the existing pathophysiology of osteoporosis. The microbiota of the intestinal tract may also affect the progression of bone loss in patients with chronic liver disease. Recently, studies regarding the effects of chronic inflammation on dysbiosis in bone diseases have been conducted. However, mechanisms underlying osteoporosis in patients with chronic liver disease are complex and precise mechanisms remain unknown. The following special considerations in patients with chronic liver disease are reviewed: bone diseases in patients who underwent a liver transplant, the association between chronic hepatitis B virus infection treatment and bone diseases, the association between sarcopenia and bone diseases in patients with chronic liver disease, and the association between chronic liver disease and avascular necrosis of the hip. Few guidelines are currently available for the management of low bone mineral density or bone diseases in patients with chronic liver disease. Due to increased life expectancy and therapeutic advances in chronic liver disease, the importance of managing osteoporosis and other bone diseases in patients with chronic liver disease is expected to increase. Consequently, specific guidelines need to be established in the near future.
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Affiliation(s)
- Hae Min Jeong
- Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24253, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Gangwon-do 24253, Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Gangwon-do 24253, Korea.
- Department of Internal Medicine, Hallym University College of Medicine, Seoul 05355, Korea.
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Abstract
The endocrine system is a complex interconnected system of organs that control corporeal processes and function. Primary endocrine organs are involved in hormonal production and secretion but rely on a bevy of signals from the hypothalamic-pituitary axis and secondary endocrine organs, such as the liver. In turn, proper hepatic function is maintained through hormonal signaling. Thus, the endocrine system and liver are codependent, and diseases affecting either organs can lead to alterations in function within their counterparts. This article explores the hepato-endocrine relationship, including the effects on endocrine diseases on the liver.
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Affiliation(s)
- Miguel Malespin
- Department of Medicine, University of Florida Health, 4555 Emerson Street, Suite 300, Jacksonville, FL 32207, USA.
| | - Ammar Nassri
- Department of Medicine, University of Florida Health, 4555 Emerson Street, Suite 300, Jacksonville, FL 32207, USA
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Abstract
A variety of rheumatologic disorders may affect the liver. There is a significant epidemiologic, genetic, and immunologic overlap between immune-mediated rheumatologic disorders and autoimmune liver diseases. There is an increased frequency of autoimmune liver diseases, such as primary biliary cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, or overlap syndrome, in patients with systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, vasculitis, and other immune-related diseases. Non-immune-mediated rheumatologic diseases such as gouty arthritis may also have hepatic manifestations. Furthermore, medications used to treat rheumatologic diseases occasionally cause liver dysfunction. Conversely, primary immune-mediated and non-immune-mediated liver disorders may present with rheumatologic manifestations.
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Affiliation(s)
- Agazi Gebreselassie
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Howard University Hospital, 2041 Georgia Avenue Northwest, Suite 4J19, Washington, DC 20060, USA
| | - Farshad Aduli
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Howard University Hospital and College of Medicine, 2041 Georgia Avenue Northwest, Suite 5C22, Washington, DC 20060, USA
| | - Charles D Howell
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Howard University Hospital and College of Medicine, 2041 Georgia Avenue Northwest, Suite 5C02, Washington, DC 20060, USA.
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Colangelo L, Biamonte F, Pepe J, Cipriani C, Minisola S. Understanding and managing secondary osteoporosis. Expert Rev Endocrinol Metab 2019; 14:111-122. [PMID: 30735441 DOI: 10.1080/17446651.2019.1575727] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/22/2019] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The term secondary osteoporosis (SO) identifies a reduction of bone mass related to a well-established disease or pharmacological agent. The identification of the underlying disease often represents a challenging situation in clinical practice. AREAS COVERED The prevalence of SO in the real world may vary, ranging from 17% to 80%; therefore, search for a form of SO represents a pillar when evaluating patients with osteoporosis. Guidelines for treatment of specific secondary forms of osteoporosis, such as glucocorticoid-induced osteoporosis, have been published even though often neglected in clinical practice. For the majority of SO, there are currently no specific guidelines concerning treatment with only few trials showing the effect of bone-active drugs on fracture risk reduction. EXPERT OPINION Healthcare professionals should be aware of the secondary forms of osteoporosis, in particular when the reason for reduced skeletal resistance is uncertain or when bone mineral density results are unsatisfactory in a patient compliant to therapy. In a few cases (such as, for example: no response to therapy, better classification of bone involvement in patients with kidney failure, suspicion of rare metabolic bone disease) bone biopsy is needed to investigate the patient. This review highlights recent advances in understanding and managing SO.
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Affiliation(s)
- Luciano Colangelo
- a Department of Internal Medicine and Medical Disciplines , "Sapienza" University of Rome , Rome , Italy
| | - Federica Biamonte
- a Department of Internal Medicine and Medical Disciplines , "Sapienza" University of Rome , Rome , Italy
| | - Jessica Pepe
- a Department of Internal Medicine and Medical Disciplines , "Sapienza" University of Rome , Rome , Italy
| | - Cristiana Cipriani
- a Department of Internal Medicine and Medical Disciplines , "Sapienza" University of Rome , Rome , Italy
| | - Salvatore Minisola
- a Department of Internal Medicine and Medical Disciplines , "Sapienza" University of Rome , Rome , Italy
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Wei MT, Le AK, Chang MS, Hsu H, Nguyen P, Zhang JQ, Wong C, Wong C, Cheung R, Nguyen MH. Antiviral therapy and the development of osteopenia/osteoporosis among Asians with chronic hepatitis B. J Med Virol 2019; 91:1288-1294. [PMID: 30776311 DOI: 10.1002/jmv.25433] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 02/12/2019] [Accepted: 02/15/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Recent studies have suggested a potential increase in the incidence of osteoporosis for patients receiving tenofovir disoproxil fumarate (TDF), but this issue remains controversial. METHODS The retrospective cohort study of 1224 Asian chronic hepatitis B (CHB) patients greater than 18 years without baseline osteopenia/osteoporosis seen at four US centers from 2008 to 2016. Patients were categorized into three groups-treatment-naive patients who initiated therapy with TDF (1) or entecavir (ETV) (2), or untreated patients (3). Patients were followed until the development of osteopenia/osteoporosis or end of the study. RESULTS Of the 1224 study patients, 276 were treated with TDF, 335 with ETV, and 613 were untreated. The prevalence of cirrhosis was lower for untreated patients (2.6% vs 16.3% for TDF and 17.6% for ETV; P < 0.001). The 8-year cumulative incidence rate of osteopenia/osteoporosis was 13.17% for TDF, 15.09% for ETV, and 10.17% for untreated patients, with no statistically significant difference among the three groups ( P = 0.218). On multivariate Cox regression controlling for demographics, osteoporosis risk factors, albumin, and hepatitis B virus (HBV) DNA levels, neither TDF (adjusted hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.34 and 1.59) nor ETV (adjusted HR = 0.98; 95% CI: 0.51 and 1.90) were associated with increased osteopenia/osteoporosis risk compared with untreated patients. CONCLUSIONS Our retrospective study suggests that there is no significant increase in the incidence of osteopenia/osteoporosis for patients with CHB treated with TDF or ETV during a median follow-up of about 4 to 5 years. However, further study with longer follow-up is needed as an anti-HBV therapy, which is often lifelong or long-term and the development of osteopenia/osteoporosis can be a slow process.
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Affiliation(s)
- Mike T Wei
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | - An K Le
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | - Matthew S Chang
- Department of Gastroenterology, Kaiser Permanente, Northern California, Santa Clara, California
| | - Holden Hsu
- Department of Medical Research, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Pauline Nguyen
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | | | - Chris Wong
- C. Wong Clinic, San Francisco, California
| | | | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
| | - Mindie H Nguyen
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
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Hayashi M, Abe K, Fujita M, Okai K, Takahashi A, Ohira H. Association between sarcopenia and osteoporosis in chronic liver disease. Hepatol Res 2018; 48:893-904. [PMID: 29734510 DOI: 10.1111/hepr.13192] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 04/13/2018] [Accepted: 05/01/2018] [Indexed: 12/13/2022]
Abstract
AIM Sarcopenia and osteoporosis are important complications in chronic liver disease (CLD). The aim of this study was to investigate the relationship between sarcopenia and osteoporosis in patients with CLD. METHODS We retrospectively investigated the relationship between sarcopenia and osteoporosis in 112 CLD patients (57 men and 55 women), including 40 cirrhotic patients (36%), by measuring the appendicular skeletal muscle mass index (ASMI) using bio-impedance analysis. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. RESULTS The sarcopenia rate was 13% (14/112), and the osteoporosis and osteopenia rates were 17% (19/112) and 65% (73/112), respectively. The rate of osteoporosis was significant and high in patients with sarcopenia or cirrhosis. In linear regression analysis, sarcopenia was significantly associated with the BMD of the lumbar spine (coefficient = -0.149, P = 0.014) and the femur neck (coefficient = -0.110, P = 0.003). Cirrhosis was also significantly associated with low BMD of the lumbar spine (coefficient = -0.160, P < 0.001) and the femur neck (coefficient = -0.066, P = 0.015). In the logistic analysis, sarcopenia (odds ratio = 6.16, P = 0.039) and cirrhosis (odds ratio = 15.8, P = 0.002) were independent risk factors for osteoporosis. The ASMI cut-off values for osteoporosis were 7.33 kg/m2 in men and 5.71 kg/m2 in women. CONCLUSIONS Sarcopenia was closely associated with osteoporosis, and a low ASMI was a potential predictor of osteoporosis in CLD patients. Screening for BMD might be required to detect osteoporosis in cirrhotic patients.
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Affiliation(s)
- Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Ken Okai
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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Tominaga N, Fernandez SJ, Mete M, Shara NM, Verbalis JG. Hyponatremia and the risk of kidney stones: A matched case-control study in a large U.S. health system. PLoS One 2018; 13:e0203942. [PMID: 30240426 PMCID: PMC6150503 DOI: 10.1371/journal.pone.0203942] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 08/11/2018] [Indexed: 12/13/2022] Open
Abstract
Kidney stones impose a large and increasing public health burden. Previous studies showed that hyponatremia is associated with an increased risk of osteoporosis and bone fractures, which are also known to be associated with kidney stones. However, the relation between hyponatremia and kidney stones is not known. To assess the relation between hyponatremia and kidney stones, we designed a matched case-control study by using the electronic health records of the MedStar Health system with more than 3.4 million unique patient records as of March 2016. Data were extracted for clinical factors of patients with kidney stones (cases) and those without kidney stones (controls). Cases (n = 20,199) and controls (n = 20,199) were matched at a 1:1 ratio for age, sex, race, and the duration of encounter window. Case and control exposures for each of the hyponatremia variables were defined by serum sodium laboratory measurements reported within the encounter windows, and divided into 3 categories: prior hyponatremia, recent hyponatremia, and persistent hyponatremia. In the final conditional logistic models adjusted for potential confounders, the risk of kidney stones significantly increased in both recent and persistent hyponatremia categories: prior hyponatremia odds ratio (OR) 0.93 (95% confidence interval [CI], 0.86–1.00); recent hyponatremia OR 2.02 (95% CI, 1.76–2.32); persistent hyponatremia OR 6.25 (95% CI, 3.27–11.96). In conclusion, chronic persistent hyponatremia is a significant and clinically important risk factor for kidney stones in patients in the U.S.
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Affiliation(s)
- Naoto Tominaga
- Division of Endocrinology and Metabolism, Georgetown University Medical Center, Washington, DC, United States of America
| | - Stephen J Fernandez
- Department of Biostatistics and Biomedical Informatics, MedStar Health Research Institute, Hyattsville, MD, United States of America
| | - Mihriye Mete
- Department of Biostatistics and Biomedical Informatics, MedStar Health Research Institute, Hyattsville, MD, United States of America
| | - Nawar M Shara
- Department of Biostatistics and Biomedical Informatics, MedStar Health Research Institute, Hyattsville, MD, United States of America
| | - Joseph G Verbalis
- Division of Endocrinology and Metabolism, Georgetown University Medical Center, Washington, DC, United States of America
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Moctezuma-Velázquez C, Low G, Mourtzakis M, Ma M, Burak KW, Tandon P, Montano-Loza AJ. Association between Low Testosterone Levels and Sarcopenia in Cirrhosis: A Cross-sectional Study. Ann Hepatol 2018; 17:615-623. [PMID: 29893704 DOI: 10.5604/01.3001.0012.0930] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Sarcopenia is an independent predictor of mortality in cirrhosis. Hypogonadism is common in cirrhosis and has been associated with sarcopenia in non-cirrhotic chronic liver disease populations. The aim of this study is to investigate if sarcopenia is associated with low testosterone levels in patients with cirrhosis. MATERIAL AND METHODS This is a retrospective analysis of prospectively collected data of 211 cirrhotic patients undergoing evaluation for liver transplantation. Sarcopenia was defined by computed tomography (CT) scan using specific cutoffs of the 3rd lumbar vertebra skeletal muscle index (L3 SMI). Morning testosterone levels were obtained in all patients. RESULTS Of the 211 patients, sarcopenia was noted in 94 (45%). Testosterone levels were lower in sarcopenic patients (10.7 ± 1.1 vs. 13.7 ± 1.4 nmol/L, p = 0.03) and hypotestosteronemia was more frequent in them too (34 vs. 16%, p = 0.004). In males, those with sarcopenia had lower testosterone levels (14.6 ± 1.4 vs. 21.9 ± 1.8, p = 0.002), and the corresponding frequency of hypotestosteronemia (42 vs. 19%, p = 0.006) was also higher. There were no significant differences in female patients. There was a weak correlation between L3 SMI and testosterone levels (r 0.37, p < 0.001). On multivariable regression analysis including sex, body mass index (BMI), hypotestosteronemia, MELD and etiology of cirrhosis, only hypotestosteronemia (RR 2.76, p = 0.005) and BMI (RR 0.88, p < 0.001) were independently associated with sarcopenia. CONCLUSION Low testosterone levels are associated with sarcopenia in male cirrhotic patients. The potential therapeutic effect of testosterone to reverse sarcopenia in these patients warrants evaluation in future trials.
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Affiliation(s)
| | - Gavin Low
- Department of Radiology, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Marina Mourtzakis
- Department of Rehabilitation Medicine, University of Waterloo, Ontario, Canada
| | - Mang Ma
- Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
| | | | - Puneeta Tandon
- Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
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Mazzucchelli R, Pérez-Fernández E, Crespí N, García-Vadillo A, Rodriguez Caravaca G, Gil de Miguel A, Carmona L. Second Hip Fracture: Incidence, Trends, and Predictors. Calcif Tissue Int 2018; 102:619-626. [PMID: 29159516 DOI: 10.1007/s00223-017-0364-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 11/09/2017] [Indexed: 10/18/2022]
Abstract
Older persons who have suffered a hip fracture (HFx) are at increased risk of subsequent hip fractures. The cumulative incidence of a second hip fracture (SHFx) has been estimated in 8.4%; however, no studies have been carried out in our country, and the information on risk markers of SHFx is limited. The aim of this study was to estimate the incidence, explore trends, and examine predictors of SHFx in a suburban population of Spain. An observational longitudinal retrospective study was performed in a universal health coverage setting (Alcorcón, 1999-2011). Data were obtained from the area hospital discharge database. Annual incidence of HFx was estimated over 100,000 population (general and persons with HFx), and median time to SHFx by Kaplan-Meier tables. Cox regression was used for the analysis of association between SHFx and baseline predictors, measured by hazard ratio (HR). Among the 3430 patients who suffered a first HFx in the study period, 255 (7.4%) experienced a SHFx (4.5% of men and 8.5% of women). Median time between the first and second HFx was 3.7 years (SD 3.2). Annual incidence of HFx in population over 45 was 290.5 per 100,000 inhabitants (131.03 in men and 433.11 in women). Annual incidence of SHFx among persons with a HFx was 956.7 per 100,000 (1052.1 in women and 595.5 in men). There was a decline trend along the study period with an annual reduction of 10.4% (95% CI 7.7-13.0%; p < 0.001) in both sexes. The following associations were found: female sex (HR 1.41, 95% CI 0.97-2.02), age (HR 1.03, 95% CI 1.01-1.04), living in a nursing house (HR 1.46, 95% CI 1.10-1.94), and moderate to severe liver disease (HR 4.96, 95% CI 1.23-20.06). In our environment the occurrence of a SHFx is 7.4%, three-fold risk compared to no previous HFx. Being woman, elderly, living in a nursing home, and having severe to moderate liver disease may be important predictors of a SHFx. There seems to be adequate time between the first and the SHFx for interventions that may reduce the risk.
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Affiliation(s)
- Ramón Mazzucchelli
- Department of Rheumatology, Hospital Universitario Fundación Alcorcón, Madrid, Spain.
| | - Elia Pérez-Fernández
- Department of Clinical Investigation, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | | | | | - Gil Rodriguez Caravaca
- Department of Preventive Medicine and Public Health, Universidad Rey Juan Carlos, Madrid, Spain
| | - Angel Gil de Miguel
- Department of Preventive Medicine and Public Health, Universidad Rey Juan Carlos, Madrid, Spain
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Adefovir dipivoxil induced hypophosphatemic osteomalacia in chronic hepatitis B: a comparative study of Chinese and foreign case series. BMC Pharmacol Toxicol 2018; 19:23. [PMID: 29769119 PMCID: PMC5956546 DOI: 10.1186/s40360-018-0212-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 04/30/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Adefovir dipivoxil (ADV)-induced renal tubular dysfunction and hypophosphatemic osteomalacia (HO) have been given great consideration in the past few years. However, no standard guidance is available due to a lack of powerful evidence from appropriate long-term prospective case-control studies and variations in the definition of renal adverse events. The aim of this study is to clarify clinical features of ADV-related HO in Chinese chronic hepatitis B patients with long-term ADV treatment in Chinese and non-Chinese comparative case series. METHODS Retrieval of case reports was based on Pubmed, CNKI, Wan Fang and VIP databases using the key words adefovir dipivoxil, hypophosphatemia, osteomalacia and Fanconi syndrome. We divided patients into Chinese (C group) and Foreign (F group) groups according to their nationality. Comparisons involving demographics, clinical manifestations, tests, treatment and prognosis were conducted between the two groups. RESULTS Of the patients screened, 120 Chinese patients were identified in the C group, and 32 non-Chinese patients were identified in the F group. The average age of the C group was younger than that of the F group (51.89 years ±10.96 years versus 56.47 years ±11.36 years, t = - 2.084, P = 0.039). No significant difference was found in gender (male to female, 3.29:1 versus 3:1, χ 2 = 0.039, P = 0.844). Although there was no significant difference in the duration of ADV therapy before ostalgia onset, the C group tended to develop adverse events earlier, by 2-3 years, while the F group developed adverse events at 4-5 years (Z = - 1.517, P = 0.129). Prognosis was good after adjustment of the ADV dose and supplemental administration of phosphate and calcitriol. Time to resolution of tubular dysfunction was commenced at the first month, and Chinese patients were more prone to recover in the first 3 months than non-Chinese patients (91.3% of patients in the C group versus 56.3% in the F group, Z = - 3.013, P = 0.003). CONCLUSIONS Sufficient attention is required for middle-aged males before and during exposure to long-term ADV therapy, regardless of nationality. The clinical picture, laboratory and radiograph alterations are important clues for those patients and are usually characterized by polyarthralgia, renal tubular dysfunction and mineralization defects. Implementation of an early renal tubular injury index is recommended for patients with higher risk, which would prevent further renal injury.
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Liao CY, Chung CH, Chu P, Wei KY, Feng TM, Lin FH, Tsao CH, Wu CC, Chien WC. Increased risk of osteoporosis in patients with primary biliary cirrhosis. PLoS One 2018; 13:e0194418. [PMID: 29543880 PMCID: PMC5854410 DOI: 10.1371/journal.pone.0194418] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 03/04/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND We evaluated the risk of osteoporosis in patients with primary biliary cirrhosis (PBC) using a nationwide population-based dataset. METHODS In a cohort study of 986,713 individuals, we selected 2,493 PBC patients who were aged 18 years or older and had been diagnosed with PBC, based on the International Classification of Disease (ICD-9-CM) codes 571.6, during 20002010. The control cohort comprised 9,972 randomly selected, propensity matched patients (by age, gender, and index date), without PBC. Using this adjusted data, a possible association between PBC and the risk of developing osteoporosis was estimated using a Cox proportional hazard regression model. RESULTS During the follow-up period, osteoporosis was diagnosed in 150 (6.02%) patients in the PBC cohort and in 539 (5.41%) patients in the non-PBC cohort. After adjusting for covariates, osteoporosis risk was found to be 3.333 times greater in the PBC cohort than in the non-PBC cohort when measured over 6 years after PBC diagnosis. Stratification revealed that the use of ursodeoxycholic acid (UDCA) had no significance in decreasing the risk of osteoporosis when comparing the PBC cohorts with the non-PBC cohorts (P = 0.124). Additionally, osteoporosis risk was significantly higher in PBC patients with steroid use (aHR: 6.899 vs 3.333). Moreover, when comparing the PBC cohorts to the non-PBC cohorts, the non-cirrhotic patients were prone to osteoporosis at a younger age compared to those in the cirrhotic cohorts. We also found that the associated risk of fractures is only prominent for vertebral and wrist fractures in the PBC cohort compared to that in the non-PBC cohort. CONCLUSION A significant association exists between PBC and subsequent risk for osteoporosis. Therefore, PBC patients, particularly those treated with steroids, should be evaluated for subsequent risk of osteoporosis.
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Affiliation(s)
- Chen-Yi Liao
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan
| | - Pauling Chu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Kuang-yu Wei
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tseng-Min Feng
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Chang-Huei Tsao
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Chao Wu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
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Assessment of bone mineral density in patients with cirrhosis treated with third-generation nucleos(t)ide analogues: comparison between tenofovir and entecavir. Eur J Gastroenterol Hepatol 2018; 30:284-290. [PMID: 29309397 DOI: 10.1097/meg.0000000000001051] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIM Tenofovir and entecavir are nowadays the first-line treatment in hepatitis B virus (HBV)-related cirrhosis. Both drugs were shown to be effective in HBV suppression and well tolerated. The effects of tenofovir on bone mineral density (BMD), however, were shown to worsen the rate of osteoporosis, which is already a common feature in cirrhosis. In contrast, entecavir seems to have no effect on mineral metabolism. The aim of our study was to compare the effects of nucleos(t)ide analogs on bone density in HBV-related cirrhosis. PATIENTS AND METHODS Fourty-eight patients were treated with tenofovir and 22 patients were treated with entecavir, and were followed prospectively from 2008 to 2013. To evaluate BMD, laboratory examinations, dual-X-ray absorptiometry, and Fracture Risk Assessment Tool were assessed. RESULTS During the study, no difference was found between the two groups in the plasmatic concentration of calcium, phosphate, vitamin D, parathyroid hormone, or creatinine. Dual-X-ray absorptiometry showed no difference in the T-score and Fracture Risk Assessment Tool showed no significant difference in the 10-year risk of osteoporotic fractures in the two groups. On univariate and multivariate analyses, the only predictors of osteoporosis development were the prognostic scores of liver disease and BMI. CONCLUSION Both tenofovir and entecavir are effective in treating HBV in cirrhotic patients. The known effects of tenofovir on BMD do not worsen osteoporotic fractures risk compared with entecavir in these patients.
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Selmi C, Generali E, Gershwin ME. Rheumatic Manifestations in Autoimmune Liver Disease. Rheum Dis Clin North Am 2018; 44:65-87. [PMID: 29149928 DOI: 10.1016/j.rdc.2017.09.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Gohil P, Patel V, Deshpande S, Chorawala M, Shah G. Anti-arthritic activity of cell wall content of Lactobacillus plantarum in freund's adjuvant-induced arthritic rats: involvement of cellular inflammatory mediators and other biomarkers. Inflammopharmacology 2017; 26:171-181. [PMID: 28685302 DOI: 10.1007/s10787-017-0370-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 06/20/2017] [Indexed: 12/17/2022]
Abstract
Alteration of microbiota is related with rheumatoid arthritis (RA) and administration of certain probiotics showed an improvement in RA. The present study was designed to find out the anti-arthritic activity of cell wall content of Lactobacillus plantarum in complete Freund's adjuvant (CFA)-induced arthritis in rats. Freund's adjuvant was injected into the left footpad in female rats on day 0 and dexamethasone (1 mg kg-1, s.c.) & cell wall content of L. plantarum (105, 107, and 109 cfu/animal, s.c.) treatment were given from day 7 to 21. The change in body weight, paw volume and arthritic index, joint stiffness, gait test, mobility test, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, serum rheumatoid factor (RF), and serum TNF-α was measured on day 21. Cell wall content of L. plantarum treated animals showed improvement in all the parameters as compared to that in CFA-treated animals and exert anti-arthritic activity.
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Affiliation(s)
- Priyanshee Gohil
- Department of Pharmacology and Clinical Pharmacy, K.B. Institute of Pharmaceutical Education and Research, GH/6, Sector-23, Gandhinagar, Gujarat, India.
| | - Vimal Patel
- Department of Pharmacology and Clinical Pharmacy, K.B. Institute of Pharmaceutical Education and Research, GH/6, Sector-23, Gandhinagar, Gujarat, India
| | - Shrikalp Deshpande
- Department of Pharmacology and Clinical Pharmacy, K.B. Institute of Pharmaceutical Education and Research, GH/6, Sector-23, Gandhinagar, Gujarat, India
| | - Mehul Chorawala
- Department of Internal medicine, University of Iowa, Iowa city, Iowa, 52246, USA
| | - Gaurang Shah
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
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