From holoprosencephaly to osteopathology: role of multifunctional endocytic receptors in absorptive epithelia

Megalin and cubilin are two multifunctional endocytic receptors expressed in many absorptive epithelia including the yolk sac, the renal proximal tubules, and the intestine. In these tissues, the receptors act in concert to mediate the cellular uptake of a variety of lipoproteins and vitamin/carrier complexes. Recent studies in animal models and in patients suffering from receptor gene defects have highlighted the crucial role played by the receptors in systemic lipid and vitamin homeostasis, and the severe defects that result from receptor dysfunction. Here, we will review the molecular mechanisms that underlie normal receptor activity and that cause disease in the receptor-deficient organism.     

Acquired hypophosphatemia osteomalacia associated with Fanconi’s syndrome in Sjögren’s syndrome

Sjögren’s syndrome is an autoimmune disorder involving exocrine glands that occurs alone or in association with various autoimmune and connective tissue diseases. The severity of Sjögren’s syndrome ranges from isolated sicca syndrome to severe complications such as vasculitis, lung and renal involvement. Overt or latent renal tubular acidosis caused by autoimmune tubulointerstitial nephritis, is a common extraglandular manifestation in Sjögren’s syndrome. Osteomalacia is a rare complication of renal tubular acidosis, and it was reported to be associated with distal renal tubular acidosis in Sjögren’s syndrome. We report a 60-year-old woman who presented with multiple bone deformity and general muscle weakness. Osteomalacia was secondary to Fanconi’s syndrome, and the Fanconi’s syndrome was a result of renal involvement in Sjögren’s syndrome. Fanconi’s syndrome is a rare kidney manifestation in Sjögren’s syndrome. It may be latent and may precede the subjective sicca symptoms. These findings suggest that evidence for Sjögren’s syndrome should be sought in adult patients with unexplained osteomalacia and renal tubular acidosis, even in the absence of subjective sicca syndrome. Conversely, in patients with Sjögren’s syndrome, early investigation and treatment of renal tubular dysfunction may prevent future complications, such as osteomalacia.     

原发性干燥综合征合并肾小管酸中毒并发骨软化症的临床特征及诊治

目的探讨原发性干燥综合征、肾小管酸中毒并发骨软化症的临床特点和治疗效果。方法回顾性分析天津医科大学总医院内分泌科2003—2008年收治的20例原发性干燥综合征、肾小管酸中毒并发骨软化症患者的临床资料。结果 20例患者均有龋齿、乏力、骨痛,15例患者有口干症状,10例患者有眼干症状。依据临床表现、骨X线和骨密度检查结果,20例患者分为严重骨病组(10例)和轻度骨病组(10例)。对比两组风湿免疫指标:严重骨病组SSA阳性率、SSB阳性率及球蛋白水平高于轻度骨病组,但差异无统计学意义(P>0.05);严重骨病组ANA、类风湿因子和γ球蛋白水平高于轻度骨病组,差异有统计学意义(P<0.05)。肾脏和肌肉组织活检均可见淋巴细胞浸润和免疫复合物沉积。治疗后无力、骨痛显著缓解。结论继发于原发性干燥综合征、肾小管酸中毒的骨软化症,除了传统的纠酸补钙治疗外,仍需积极的免疫抑制治疗和补充足量的活性维生素D。     

氟铝联合中毒小鼠骨骼病理与形态计量学研究

目的 探讨氟铝联合中毒小鼠骨相组织病变特征及致病的可能机制.方法 采用析因设计方法,将昆明种小鼠分成9组,由氟化钠(NaF,0、50、150 mg/L)、氯化铝(AlCl3,0、200、600mg/L)经饮水染毒,24周后对斑釉牙发生情况进行分度,测量股骨下端骨骺的骨小梁面积、类骨质面积,计数成骨细胞和破骨细胞个数,并观察骨组织病理变化.结果 铝单独作用也可引起斑釉牙(分度为4度),氟铝联合对牙的损害比各自单独作用严重.氟铝共存对骨小梁面积和类骨质面积的影响存在交互作用(F值分别为2.963、3.688,P＜0.05),对成骨细胞和破骨细胞数的影响不存在交互作用(F值分别为2.347、0.888,P＞0.05).高氟组骨小梁面积、类骨质面积为(50675.47±22 916.34)、(10 733.97±3015.55)μm2,高氟高铝组升高到(75 988.64±13 797.21)、(16 402.88±4605.83)μm2(P＜0.05),高氟低铝组升高到(69 277.16 ±19 837.51)、(18 564.79 4-6362.47)μm2(P＜0.05),铝拮抗了氟的效应;高铝组骨小梁面积为(60 718.43 4-17 574.37)μm2,高氟高铝组[(75 988.64 ±13 797.21)μm2]、低氟高铝组[(82 474.94±15 466.6)μm2]均升高(P＜0.05),联合作用效应与高剂量铝的作用趋势一致.骨组织病理改变为骨质疏松明显,类骨质和软骨组织增多,骨基质和矿化骨减少.结论 高剂量的铝和氟均可引起斑釉牙,联合作用比单一因素作用强.氟铝联合中毒对骨骼的影响以软化型骨质疏松为主要特征.     

阿德福韦酯致肾小管损害继发低磷软骨症5例并文献分析

目的探讨阿德福韦酯(10 mg/d)长期治疗慢性乙肝患者引起肾小管损害继发低磷软骨症的临床特点、治疗方法及预后。方法回顾性分析2011年11月至2013年11月我院内分泌科收治的5例阿德福韦酯致肾小管损害继发低磷软骨症患者的临床表现、实验室检查、影像学检查、治疗方案以及随访情况,并通过检索Pub M ed、中国知网全文数据库,结合相关文献报道病例进行比较分析。结果我院5例患者的临床表现主要为骨痛进行性加重;实验室检查主要为低血磷、高尿磷、高碱性磷酸酶(ALP)、低血钙。治疗方法:5例患者停用阿德福韦酯,加用碳酸钙D3及骨化三醇,4例给予补充中性磷溶液,2~8个月血磷正常,骨痛缓解。结论低剂量阿德福韦酯会引起低磷软骨症,建议长期用药的患者定期监测尿酸、肾小球滤过率(e GFR)、ALP、血磷、尿常规等,服药期间一旦出现不明原因的骨痛也应及时就医,以便尽早确诊,尽早停药治疗并对症处理。     

低血磷性骨软化症七例报告

目的：通过分析罕见代谢性骨病低血磷性骨软化症的临床表现、辅助检查与疗效,对低血磷性骨软化症诊断提供参考,减少误诊和漏诊。方法回顾性分析2000年至2013年于我院诊治的7例“低血磷性骨软化症”患者,对其临床表现、辅助检查情况和疗效特点进行分析,并归纳总结其共同点。结果7例共同特点：(1)因早期症状无特异性,均被不同程度误诊,平均误诊(1.2±0.5)年;(2)症状表现为全身多发不明原因骨痛、肌无力,可伴多发骨折,甚至骨畸形;(3)实验室检查可见显著低血磷,但血钾正常,肿瘤致该病患者经查体结合SPECT检查可发现致病肿瘤;(4)在确诊后,对散发性低血磷性骨软化症者给予中性磷合剂、药物性低血磷性骨软化症者停药后补磷、肿瘤相关性低磷性骨软化症( tumor-induced osteomalacia, TIO)手术去除肿瘤后,血磷水平均上升,病情明显改善,预后较好。结论低血磷性骨软化症者常表现为低血磷,并伴全身多发不明原因骨痛、肌无力,可伴多发骨折,甚至骨畸形。临床医生应进一步提高对该疾病的认识,通过实验室以及影像学检查,可提高确诊率,减少误诊和漏诊。对于确诊的病例找到病因后,给予适当治疗,患者的病情可得到相当程度的改善。     

高铝高氟骨变形患者骨质改变的显微CT检查结果分析

目的 分析高铝高氟骨变形患者骨质改变的显微CT检查结果.方法 在贵州省水城县农村勺米乡与纸厂乡结合部燃煤污染型地方性氟中毒(简称地氟病)病区,以骨变形儿童、青年、中年氟骨症患者作为病例组观察对象,同时以病区非骨变形儿童、青年,以及非病区儿童作为对照.通过矫形手术和病因学检查获得髂前上棘和胫骨上段骨组织,进行不脱钙树脂包埋.采用显微CT检查扫描树脂包埋的骨组织,用ABA专用骨骼分析软件INVEON reseach workplace和Micview三维重建处理软件分析相关参数.结果 ①髂前上棘松质骨:病区骨变形儿童与病区非骨变形儿童比较,骨小梁相对体积(0.337％比0.229％)、绝对厚度(μm:139比133)、单位长度内骨小梁的数量(个/mm:2.44比1.72)、骨小梁密织度(个/mm:2.22比1.54)和骨矿密度(mg/cm3:1 033比918)均有增高趋势,而骨小梁相对骨面积(mm2/mm3:14.5比15.1)、空间间距(μm:0.274比0.567)有降低趋势.病区骨变形青年与病区非骨变形青年比较,骨小梁相对体积较低(0.217％比0.437％),相对面积增加(mm2/mm3:16.9比11.6),绝对厚度降低(μm:118比172),单位长度内的骨小梁数量减少(个/mm:1.83比2.54),空间间距增大(μm:0.427比0.222),但骨小梁密织度增加(个/mm:4.61比1.54),骨矿密度下降(mg/cm3:977比1 108),呈骨量减少、骨质疏松、骨矿减少,骨小梁交叉数量增多的细疏结构.②胫骨上段骨组织:病区骨变形儿童与非病区儿童比较,胫骨上段密质骨骨小梁相对体积增高(0.435％比0.206％),骨小梁相对面积(mm2/mm3:12.3比12.4)、绝对厚度(μm:188比161)改变不明显,单位长度内的骨小梁数量增加(个/mm:2.43比1.28),空间间距减小(μm:0.238比0.621),骨小梁密织度减少(个/mm:2.40比3.48),骨矿密度增加(mg/cm3:1 047比952),呈骨小梁增粗、数量增加和骨矿增多的粗密结构.病区中年氟骨症患者与非病区儿童比较,骨小梁相对体积(0.346％比0.206％)和面积(mm2/mm3:13.8比12.4)增加,绝对厚度减少(μm:144比161),单位长度内的骨小梁数量增加(个/mm:1.98比1.28),空间间距减小(μm:0.318比0.621),骨小梁密织度减少(个/mm:2.60比3.48).结论 铝氟联合作用在不同发育阶段人体骨组织的效应不同,高铝高氟负荷性作用于发育前的儿童,表现为骨小梁粗大密集,呈骨量增加和骨矿沉积增多的骨硬化影像;骨变形青年表现为骨量减少的骨质疏松、骨矿沉积减少.中年氟骨症患者骨量略增多、骨小梁数量增多、骨小梁呈细密结构.     

Adult hypophosphatemic osteomalacia: report of two cases

Summary Two cases of late hypophosphatemic osteomalacia are described: a male aged 30 who had the disease since he was 22 and a woman of 23 who had the disease since she was 14. Both presented with myopathy and bone pain, and showed hypophosphatemia, hyperglycinuria, reduced tubular phosphate reabsorption (TPR), increased hydroxyprolinuria and normal iPTH and iCT values. Radiologically the male had no Looser's zones and the woman did. Bone biopsy confirmed hypophosphatemic osteomalacia. Both cases were treated with vitamin D and oral phosphate and no improvement was observed. When treatment with 25(OH)D3 was initiated, no improvement was seen and afterwards this was combined with treatment using 1.25(OH)2D3 and from this time on a clinical improvement of the myopathy became evident in both patients. In the woman, healing of the bone lesions occurred at the same time as that of the myopathy, whereas in the male the bone lesions became worse. Healing of the myopathy was only obtained when treatment with 1.25(OH)2D3 was begun. Both patients had reduced values of 2.3 erythrocytic DPG and low level of serum phosphorus when the myopathy was cured, which suggests a lack of effect of 2.3 DPG or serum phosphorus as a cause of the myopathy. Although this had been attributed to a deficiency in the function of 25(OH)D3, the response to 1.25(OH)2D3 and due to the effects of this metabolite on calcium transport in muscle, suggests that the myopathy which occurs in late hypophosphatemic osteomalacia is a result of deficiency or resistance to the muscular effect of this metabolite. We cannot explain the lack of bone healing in the man and further therapeutic studies are required.