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

Bihari, Chhagan; Lal, Deepika; Thakur, Monika; Sukriti, Sukriti; Mathur, Dhananjay; Patil, Anupama; Anand, Lovkesh; Kumar, Guresh; Sharma, Shvetank; Thapar, Shalini; Rajbongshi, Apurba; Rastogi, Archana; Kumar, Anupam; Sarin, Shiv Kumar

doi:10.1002/hep4.1234

Cited by 17 publications

(15 citation statements)

References 37 publications

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“…Although chronic liver diseases have various etiologies, including hepatitis virus, cholestasis, and alcohol consumption, patients with chronic liver disease or cirrhosis show bone loss and a high prevalence of osteoporosis, which is known as hepatic osteodystrophy (38,39). Several mechanisms of hepatic osteodystrophy have been proposed, including cytokines (e.g., transforming growth factor β, tumor necrosis factor α, and interleukin-6), vitamin D metabolism, and sex hormones (40,41). However, much is still unknown about hepatic osteodystrophy in NAFLD and nonalcoholic steatohepatitis (NASH) (40).…”

Section: Discussionmentioning

confidence: 99%

Association of Bone Metabolism with Fatty Liver Disease in the Elderly in Japan: A Community-based Study

et al. 2020

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Objective With the aging of society, both osteoporosis and fatty liver disease (FLD) are becoming important issues. However, the relationship between osteoporosis and FLD remains controversial. We investigated the association between bone metabolism and FLD in a Japanese community in a cross-sectional study. Methods A total of 1,020 participants were enrolled in a health survey. FLD was diagnosed by ultrasonography. Bone metabolism was evaluated based on bone mineral density (BMD), which was assessed using dual-energy X-ray absorptiometry, and with the bone formation index (total type I procollagen N-terminal propeptide/bone-alkaline phosphatase ratio; P1NP/BAP ratio) and the bone resorption index (crosslinked Ntelopeptide of type I collagen/tartrate-resistant acid phosphatase-5b ratio; NTx/TRACP-5b ratio) calculated from serum bone turnover markers. Results The BMD (percentage of the young adult mean) was the same level in both male and female participants with and without FLD. Both men and women showed an age-dependent decrease in their bone formation index and bone resorption index values. Men of ! 70 years of age and women of 60-69 years of age with FLD had significantly lower bone formation index values and higher bone resorption index values. However, similar findings were not seen in women of ! 70 years of age. Conclusion Although the BMD levels were the same, regardless of the presence or absence of FLD, elderly participants with FLD showed decreased bone formation and increased bone resorption, with sex differences. Because our results suggest that FLD in elderly individuals is detrimental for bone metabolism, and that it leads to bone loss and osteoporosis, further studies using a cohort population are warranted.

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Section: Discussionmentioning

confidence: 99%

Association of Bone Metabolism with Fatty Liver Disease in the Elderly in Japan: A Community-based Study

et al. 2020

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“…Reduced PTH levels on the other hand may increase FGF-23 expression in bone cells [134], which stimulates bone turnover by enhancing VitD metabolism both positively and negatively via inhibition of CYP27B1 and induction of CYP24A1 [97]. FGF-23 serum levels are reported to be increased in patients with CLD [141,142,143]. This may explain why increased PTH levels are negatively associated with secondary osteoporosis in these patients [12,143,144] (Figure 2).…”

Section: Alterations In Vitamin D and Calcium In Patients With Cldmentioning

confidence: 99%

“…FGF-23 serum levels are reported to be increased in patients with CLD [141,142,143]. This may explain why increased PTH levels are negatively associated with secondary osteoporosis in these patients [12,143,144] (Figure 2).…”

Section: Alterations In Vitamin D and Calcium In Patients With Cldmentioning

confidence: 99%

Hepatic Osteodystrophy—Molecular Mechanisms Proposed to Favor Its Development

Ehnert¹,

Aspera-Werz²,

Ruoß³

et al. 2019

IJMS

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Almost all patients with chronic liver diseases (CLD) show altered bone metabolism. Depending on the etiology, this manifests in a severe osteoporosis in up to 75% of the affected patients. Due to high prevalence, the generic term hepatic osteodystrophy (HOD) evolved, describing altered bone metabolism, decreased bone mineral density, and deterioration of bone structure in patients with CLD. Once developed, HOD is difficult to treat and increases the risk of fragility fractures. Existing fractures affect the quality of life and, more importantly, long-term prognosis of these patients, which presents with increased mortality. Thus, special care is required to support the healing process. However, for early diagnosis (reduce fracture risk) and development of adequate treatment strategies (support healing of existing fractures), it is essential to understand the underlying mechanisms that link disturbed liver function with this bone phenotype. In the present review, we summarize proposed molecular mechanisms favoring the development of HOD and compromising the healing of associated fractures, including alterations in vitamin D metabolism and action, disbalances in transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signaling with histone deacetylases (HDACs) as secondary regulators, as well as alterations in the receptor activator of nuclear factor kappa B ligand (RANKL)–osteoprotegerin (OPG) system mediated by sclerostin. Based on these mechanisms, we give an overview on the limitations of early diagnosis of HOD with established serum markers.

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“…Earlier, we have shown the quantitative and qualitative dysfunction of the BM stem cells in advanced cirrhosis. [7,8] Other studies showed role of BM in hepatic regenerative response. [9,10] A study from our group revealed that those with early cirrhosis and su cient BM reserve could respond to GCSF.…”

Section: Introductionmentioning

confidence: 99%

CSF3-Receptor Downregulation in Bone Marrow contributes to Ineffectiveness of GCSF in Advanced Liver Cirrhosis

Bihari

Baweja

Lal

et al. 2021

Preprint

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Introduction: Cirrhosis patients exhibit cytopenia and variable response to GCSF, with benefits in early cirrhosis. GCSF acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We investigated the possible mechanism for the lack of efficacy of GCSF in advanced cirrhosisMethodsCirrhotic patients (n = 127) and controls (n = 26) who underwent clinically indicated bone marrow (BM) examination were studied. BMs were assessed for RNA sequencing, qRT-PCR, and immunohistochemistry (IHC) for CSF3R and associated genes. Circulating GCSF, CSF3R, and carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) were measured. BM hematopoietic precursor cells and their alterations were examined by flow cytometry. The findings were validated, where the GCSF was administered as for liver regeneration (n = 22) and severe neutropenia (n = 15)ResultsThe mean age was 48.6 ± 13.4 years, 80.3% males. Gene set enrichment analysis showed lowered CSF3R in Child's C compared to A, confirmed by qRT-PCR and IHC. Circulatory CSF3R was also reduced in advanced cirrhosis. CSF3R decline was related to decrease hematopoietic stem cells (HSCs) and downregulation of CSF3R in remaining HSCs. CSF3R inhibitory protein CEACAM1 caused CSF3R downregulation. CEACAM-1, in turn, positively correlated with the increased lysosomal expression in HSCs. Peripheral blood-CSF3R was lesser in those cases who developed an infection Baseline CSF3R was also lower in G-CSF non-responders.ConclusionsCSF3R is downregulated in patients with advanced cirrhosis, and it could be the underlying cause of the inadequate response to GCSF.

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

Cited by 17 publications

References 37 publications

Association of Bone Metabolism with Fatty Liver Disease in the Elderly in Japan: A Community-based Study

Association of Bone Metabolism with Fatty Liver Disease in the Elderly in Japan: A Community-based Study

Hepatic Osteodystrophy—Molecular Mechanisms Proposed to Favor Its Development

CSF3-Receptor Downregulation in Bone Marrow contributes to Ineffectiveness of GCSF in Advanced Liver Cirrhosis

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