Relationship between osteoporosis, sarcopenia, vertebral fracture, and osteosarcopenia in patients with primary biliary cholangitis.
- 作者列表："Saeki C","Oikawa T","Kanai T","Nakano M","Torisu Y","Sasaki N","Abo M","Saruta M","Tsubota A
AIM:Bone disorders are serious complications in patients with primary biliary cholangitis (PBC), especially in postmenopausal female patients. Given that osteoporosis interrelates closely with sarcopenia, the concept of osteosarcopenia (coexistence of the two complications) has been established. This study aimed to investigate the relationship between osteoporosis, sarcopenia, vertebral fracture, and osteosarcopenia in PBC patients. METHODS:This study involved 117 consecutive PBC patients (21 males and 96 females). Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry. Sarcopenia was diagnosed according to the Japan Society of Hepatology assessment criteria. RESULTS:Of the 117 patients, 33 (28.2%), 27 (23.1%), 21 (17.9%), and 18 (15.4%) had osteoporosis, sarcopenia, vertebral fracture, and osteosarcopenia, respectively. Multivariate analysis identified sarcopenia as a significant, independent risk factor associated with osteoporosis in all and female patients [odds ratio (OR) = 4.126, P = 0.018; OR = 6.510, P = 0.001, respectively], and vice versa (OR = 3.420, P = 0.040; OR = 4.012, P = 0.026, respectively). The skeletal muscle mass index and handgrip strength were significantly correlated with the BMD of the lumbar spine, femoral neck, and total hip (r = 0.46-0.59, P < 0.001). Patients with osteosarcopenia had significantly higher prevalence of vertebral fracture (10/18; 55.6%) than those without both osteoporosis and sarcopenia (5/75; 6.7%). CONCLUSION:We demonstrated the prevalence of osteoporosis, sarcopenia, vertebral fracture, and osteosarcopenia in PBC, and noted that these complications interrelated closely with each other. Comprehensive assessment and treatment strategies for bone and muscle disorders are essential for PBC patients.
目的: 骨病是原发性胆汁性胆管炎 (PBC) 患者的严重并发症，尤其是绝经后女性患者。鉴于骨质疏松症与肌肉减少症密切相关，骨质减少症 (两种并发症并存) 的概念已经建立。本研究旨在探讨 PBC 患者骨质疏松、肌肉减少症、椎体骨折和骨质减少的关系。 方法: 本研究连续纳入 117 例 PBC 患者 (男 21 例，女 96 例)。骨矿密度 (BMD) 测定双能 x线骨密度仪测定.根据日本肝病学会评估标准诊断为肌少症。 结果: 117 例患者中，33 例 (28.2%) 、 27 例 (23.1%) 、 21 例 (17.9%) 和 18 例 (15.4%) 分别患有骨质疏松症、肌肉减少症、椎体骨折和骨质减少症。多因素分析发现，在所有和女性患者中，肌少症是与骨质疏松相关的独立危险因素 [比值比 (OR) = 4.126，P = 0.018; OR = 6.510，P = 0.001,分别]，反之亦然 (OR = 3.420，P = 0.040; OR = 4.012,P = 0.026，分别)。骨骼肌质量指数、握力与腰椎、股骨颈、全髋 BMD 显著相关 (r = 0.46 ~ 0.59，P <0.001)。骨质减少症患者的椎体骨折患病率 (10/18; 55.6%) 显著高于无骨质疏松和肌肉减少症的患者 (5/75; 6.7%)。 结论: 我们证明了 PBC 中骨质疏松、肌肉减少症、椎体骨折和骨质减少的患病率，并指出这些并发症彼此密切相关。骨和肌肉疾病的综合评估和治疗策略对 PBC 患者至关重要。
METHODS:BACKGROUND & AIMS:Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) exceeds 20% and BTC is currently the leading cause of death in PSC patients. To open new avenues for management, we aimed to delineate novel and clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). APPROACH & RESULTS:We analysed formalin fixed, paraffin embedded tumor tissue from 186 PSC-BTC patients from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations and copy number variations, along with histomorphological and immunohistochemical characterization. Irrespective of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, e.g. TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g. HER2/ERBB2). We found a high frequency of non-typical/non-ductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%) CONCLUSION: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC show a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.
METHODS:BACKGROUND:The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. METHODS:One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. RESULTS:Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). CONCLUSIONS:Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.
METHODS::T cells from patients with primary sclerosing cholangitis (PSC) show a prominent IL-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant TH17 response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T cell response towards Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using trans-well experiments with cholangiocytes. Cytokine production was measured using flow cytometry, ELISA, RNA in situ hybridization and quantitative real time PCR. Genetic polymorphisms were obtained from Immunochip analysis. Following ex vivo stimulation with PMA/Ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4+ T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines CCL-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hi CD16int and CD14lo CD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis and monocytes were found to be located around bile ducts. Conclusion: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.