Bone Diseases in Patients with Chronic Liver Disease

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.

Keywords: biliary cholangitis; dysbiosis; liver cirrhosis; liver disease; liver transplantation; osteoporosis; sarcopenia; tenofovir disoproxil fumarate.

Figure 1

Pathophysiology of bone loss. Bone loss due to decreased bone formation is mostly a direct or indirect toxic effect on osteoblast differentiation and survival. In contrast, increased bone resorption resulting from the activation of osteoclasts is a cause of bone diseases in patients with chronic liver disease due to the effects of inflammation and hormones. In particular, activated immune cells such as T-lymphocytes and activated synovial fibroblasts are the primary source of receptor activator of nuclear factor κ-β ligand (RANKL), which activates osteoclasts. Activated osteoclasts secrete matrix metallopeptidases (MMP) and cathepsin K (Cat K), resulting in bone resorption. OPG: osteoprotegerin; RANK: receptor activator of nuclear factor κ-β.

Figure 2

Effects of sclerostin on osteoblast differentiation. Sclerostin produced by osteocytes inhibits Wnt/β-catenin signaling during early bone diseases in patients with cholestatic diseases [3]. This soluble protein is produced by osteocytes that differentiated from osteoblasts and prevents Wnt from binding to low-density lipoprotein receptor-related proteins-5/6 (LRP5/6) transmembrane receptors. This blockade prevents Wnt signaling and osteoblast differentiation to inhibit bone formation. LRP: lipoprotein receptor-related proteins; GSK3: glycogen synthase kinase 3, DKK: Dickkopf; sFRP: secreted frizzled-related protein; APC: adenomatosis polyposis coli; TCF: T-cell specific transcription factor.

Figure 3

Dysbiosis and gut homeostasis. Dysbiosis has been linked to increased intestinal permeability and a leaky gut. When the balance of the protective bacteria in the intestine collapses and these bacteria are replaced with harmful bacteria, the permeability of the intestinal mucosa is abnormally altered, causing the disappearance of the protective barrier and the induction of inflammation. IgA: immunoglobulin A; PRRs: pattern recognition receptors.