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Suboptimal Level of Bone-Forming Cells in Advanced Cirrhosis are Associated with Hepatic Osteodystrophy.

ABSTRACT: Bone loss is common in advanced cirrhosis, although the precise mechanisms underlying bone loss in cirrhosis are unknown. We studied the profile and functionality of bone-forming cells and bone-building proteins in bone marrow (BM) of individuals with cirrhosis (n = 61) and individuals without cirrhosis as normal controls (n = 50). We also performed dual energy X-ray absorptiometry for clinical correlation. BM mesenchymal cells (MSCs) were analyzed for colony-forming units-fibroblasts and their osteogenic (fibronectin-1 [FN1], insulin-like growth factor binding protein 3 [IGFBP3], collagen type 1 alpha 1 chain [COL1A1], runt-related transcription factor 2 [RUNX2], and alkaline phosphatase, liver [ALPL]) and adipogenic ( adiponectin, C1Q, and collagen domain containing [ADIPOQ], peroxisome proliferator-activated receptor gamma [PPAR?], and fatty acid binding protein 4 [FABP4]) potentials. Colony-forming units-fibroblasts were lower in patients with cirrhosis (P = 0.002) than in controls. Cirrhotic BM-MSCs showed >2-fold decrease in osteogenic markers. Compared to controls, patients with cirrhosis showed fewer osteocytes (P = 0.05), osteoblasts, chondroblasts, osteocalcin-positive (osteocalcin+) area, clusters of differentiation (CD)169+ macrophages (P < 0.001, each), and nestin+ MSCs (P = 0.001); this was more apparent in Child-Turcotte-Pugh (CTP) class C than A (P < 0.001). Multivariate logistic regression showed low nestin+ MSCs (P = 0.004) as a predictor of bone loss. Bone-resolving osteoclasts were comparable among CTP groups, but >2-fold decreased anti-osteoclastic and increased pro-osteoclastic factors were noted in patients with CTP C compared to CTP A. Bone-building proteins (osteocalcin [P = 0.008], osteonectin [P < 0.001], and bone morphogenic protein 2 [P = 0.001]) were decreased while anti-bone repair factors (fibroblast growth factor 23 [P = 0.015] and dipeptidyl peptidase 4 [P < 0.001]) were increased in BM and peripheral blood; this was more apparent in advanced cirrhosis. The dual energy X-ray absorptiometry scan T score significantly correlated with the population of osteoblasts, osteocytes, MSCs, and CD169+ macrophages. Conclusion: Osteoprogenitor cells are substantially reduced in patients with cirrhosis and more so in advanced disease. Additionally, increased anti-bone repair proteins enhance the ineffective bone repair and development of osteoporosis in cirrhosis. Hepatology Communications 2018;0:0-0).

SUBMITTER: Bihari C

PROVIDER: S-EPMC6128237 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Suboptimal Level of Bone-Forming Cells in Advanced Cirrhosis are Associated with Hepatic Osteodystrophy.

Bihari Chhagan C Lal Deepika D Thakur Monika M Sukriti Sukriti S Mathur Dhananjay D Patil Anupama G AG Anand Lovkesh L Kumar Guresh G Sharma Shvetank S Thapar Shalini S Rajbongshi Apurba A Rastogi Archana A Kumar Anupam A Sarin Shiv K SK

Hepatology communications 20180904 9

Bone loss is common in advanced cirrhosis, although the precise mechanisms underlying bone loss in cirrhosis are unknown. We studied the profile and functionality of bone-forming cells and bone-building proteins in bone marrow (BM) of individuals with cirrhosis (n = 61) and individuals without cirrhosis as normal controls (n = 50). We also performed dual energy X-ray absorptiometry for clinical correlation. BM mesenchymal cells (MSCs) were analyzed for colony-forming units-fibroblasts and their ...[more]

PMID: 30202823

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Project description:BACKGROUNDCirrhosis is a chronic late stage liver disease associated with hepatitis viruses, alcoholism, and metabolic disorders, such as Wilson disease (WD). There are no clear markers or clinical features that define cirrhosis originating from these disparate origins. We hypothesized that cirrhosis is not one disease and cirrhosis of different etiology may have differential clinical hepatic features.AIMTo delineate the liver features between WD-associated cirrhosis and hepatitis B-associated cirrhosis in the Chinese population.METHODSIn this observational study, we reviewed the medical data of consecutive inpatients who had WD-associated cirrhosis or hepatitis B-associated cirrhosis from January 2010 to August 2018, and excluded patients who had carcinoma, severe heart or pulmonary diseases, or other liver diseases. According to the etiology of cirrhosis, patients were divided into two groups: WD-associated cirrhosis group (60 patients) and hepatitis B-associated cirrhosis group (56 patients). The liver fibrosis degree, liver function indices, and portal hypertension features of these patients were compared between the two groups.RESULTSNo inter-group differences were observed in the diagnostic liver fibrosis markers, however, clinical features clearly defined the origin of cirrhosis. WD-associated cirrhosis patients (16-29 years) had lower levels of alanine transaminase, aspartate transaminase, and bilirubin, lower prothrombin time, lower incidence of hepatic encephalopathy, and lower portal vein diameter (P < 0.05), compared to cirrhosis resulting from hepatitis B in older patients (45-62 years). Importantly, they had decreased risks of progression from Child-Pugh grade A to B (odds ratio = 0.046, 95% confidence interval: 0.006-0.387, P = 0.005) and of ascites (odds ratio = 0.08, 95% confidence interval: 0.01-0.48, P = 0.005). Conversely, WD-associated cirrhosis patients had a higher risk of splenomegaly (odds ratio = 4.15, 95% confidence interval: 1.38-12.45, P = 0.011).CONCLUSIONWD-associated cirrhosis presents a higher risk of splenomegaly associated with leukopenia and thrombocytopenia, although revealing milder liver dysfunction and portal hypertension symptoms, which recommends WD patients to be monitored for associated complications.

Project description:A main obstacle to diagnose and manage renal osteodystrophy (ROD) is the identification of intracortical bone turnover type (low, normal, high). The gold standard, tetracycline-labeled transiliac crest bone biopsy, is impractical to obtain in most patients. The Kidney Disease Improving Global Outcomes Guidelines recommend PTH and bone-specific alkaline phosphatase (BSAP) for the diagnosis of turnover type. However, PTH and BSAP have insufficient diagnostic accuracy to differentiate low from non-low turnover and were validated for trabecular turnover. We hypothesized that four circulating microRNAs (miRNAs) that regulate osteoblast (miRNA-30b, 30c, 125b) and osteoclast development (miRNA-155) would provide superior discrimination of low from non-low turnover than biomarkers in clinical use. In 23 patients with CKD 3-5D, we obtained tetracycline-labeled transiliac crest bone biopsy and measured circulating levels of intact PTH, BSAP, and miRNA-30b, 30c, 125b, and 155. Spearman correlations assessed relationships between miRNAs and histomorphometry and PTH and BSAP. Diagnostic test characteristics for discriminating low from non-low intracortical turnover were determined by receiver operator curve analysis; areas under the curve (AUC) were compared by ?2 test. In CKD rat models of low and high turnover ROD, we performed histomorphometry and determined the expression of bone tissue miRNAs. Circulating miRNAs moderately correlated with bone formation rate and adjusted apposition rate at the endo- and intracortical envelopes (? = 0.43 to 0.51; p <?0.05). Discrimination of low versus non-low turnover was 0.866, 0.813, 0.813, and 0.723 for miRNA-30b, 30c, 125b, and 155, respectively, and 0.509 and 0.589 for PTH and BSAP, respectively. For all four miRNAs combined, the AUC was 0.929, which was superior to that of PTH and BSAP alone and together (p <?0.05). In CKD rats, bone tissue levels of the four miRNAs reflected the findings in human serum. These data suggest that a panel of circulating miRNAs provide accurate noninvasive identification of bone turnover in ROD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Dataset Information

Suboptimal Level of Bone-Forming Cells in Advanced Cirrhosis are Associated with Hepatic Osteodystrophy.

Publications

Suboptimal Level of Bone-Forming Cells in Advanced Cirrhosis are Associated with Hepatic Osteodystrophy.

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