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1、淀粉样变病,Amyloidosis,Introduction,Amyloidosis is a collective name for a series of diseases in which excess protein is deposited on various organ systems. Amyloidosis is generally classified into three groups, AL, AA, and ATTR, based upon the type of protein deposited. Finnish type amyloidosis (FAF) fa
2、lls into the ATTR, or hereditary category.,分类,原发 少见 继发 常有结核 CTD 肿瘤,病变部位,局限 全身性,心脏 最多见 血管壁 胃肠道 舌 气管、肺及胸膜 肝脾肾等,Clinical Signs,Persons with Finnish type amyloidosis may suffer from a wide range of disorders. 神经系统 include cranial neuropathy, bulbar palsy, and peripheral polyneuropathy. 眼Corneal lattice
3、dystrophy and cutis laxa may result due to local amyloid deposition. 肾Patients may also suffer from nephrotic syndrome and renal failure characteristic of other amyloid disorders.,皮肤,Amyloidosis deposition,手,喉,是常见的受累部位，为粘膜肥厚，息肉。主要症状为声嘶。,心肌淀粉样变,猝死率 15-35% 出现症状2 年内死亡 心律失常 50%低电压，1/3酷似心梗 超声心脏增厚与心电图低电压
4、同时存在是其常见表现,心肌淀粉样变,X线胸片、CT和超声 心脏大小正常，部分可有胸腔心包积液。增强CT显示为室间隔与心室壁增厚，但与肥厚性心肌病难以鉴别，而超声心动图显示为室间隔与心室壁增厚并可见较为特征性的闪烁颗粒,呼吸道淀粉样变临床,40-60岁中老年人为主 性别差异不大 发病后平均生存率为1年， 常见表现为咳嗽，气道阻塞，痰中带血，呼吸困难等，累及心脏的可出现充血性心衰。,呼吸道淀粉样变,气管-支气管型 肺结节型 单发/多发 肺泡-间隔型或间质型 弥漫病变型 3种形式可共同存在,1 气管-支气管型,1/4病例的病变为局限性 3/4为弥漫性,局限性支气管淀粉样变,气管支气管粘膜淀粉样变：
5、呼吸困难，活动后为重， 喘鸣喷嚏咯血， 肺不张,弥漫性支气管淀粉样变,影像特征,管壁波浪状不均匀弥漫增厚和（或）腔内结节，管腔环形或偏心狭窄阻塞，病变范围广，常累及多个支气管。 该型与支气管内膜结核、复发性多软骨炎、气管内肿瘤等有相似之处。,气道型放射学,CT：气管、大支气管管壁增厚或腔内肿块，管腔环形或不对称性狭窄，常合并阻塞性肺不张、肺炎或肺气肿，,2 肺结节型淀粉样变,多位于肺周围胸膜下区，症状轻,肺结节型放射学,X线胸片和CT表现为肺内单发或多发结节，多在肺下叶，以0.55.0 cm最常见，偶见斑点状钙化，极少有空洞,3 弥散型肺实质淀粉样变,最常见，进行性呼吸困难,影像征象,缺乏特异
6、性，与结缔组织病的胸部损害鉴别困难。,肺间质型放射学,X线胸片多表现为弥漫性线网状模糊影，也可表现为网状小结节影、蜂窝肺，偶有胸水 。 HRCT表现为小叶间隔增厚呈网状和（或）弥漫分布的小于5 mm的边界清晰小结节，可有钙化8。HRCT能显示该型病变的缓慢进展而X线胸片变化多不明显。,4 胸膜,受累的X线胸片和CT表现为胸膜增厚或胸膜结节，常伴胸腔积液，也有患者仅表现为胸腔积液 。本组4例既有胸膜增厚又有胸腔积液，与文献相符。,检查,胸片,气管支气管淀粉样变，纹理重，阻塞性肺炎肺不张 肺实质淀粉样变 两肺斑片/块状/多发结节影，钙化空洞， 或有肺门纵隔淋巴结大，胸膜受累 肺间质纤维化,支气管镜
7、,管壁单灶或多灶隆起或普遍狭窄，隆起呈光滑无蒂结节，大小不等，苍白上皮，有时支气管完全阻塞。,肺功能,阻塞性肺通气功能障碍，气管支气管淀粉样变 弥漫功能减低，限制性通气障碍，弥散性淀粉样变 正常肺功能，肺结节状淀粉样变,组织学,刚果红染色阳性 确诊靠病灶、骨髓、腹部脂肪、直肠黏膜等多部位组织活检。 直肠活检阳性率70%,Positive Biopsy,Amyloidosis of the kidney shown under a polarizing microscope. Congo red binds to the depositions causing green birefringen
8、ce when shown under polarized light.,镜检,继发性淀粉样变,结核，结缔组织病，骨髓瘤，淋巴瘤、慢性感染继发性：家族性，老年性，慢性感染者,多发性骨髓瘤 MM继发淀粉样变,较常见，一般认为其发生率约为6%15% ，于病程中逐渐出现舌大、腹壁皮肤增厚变硬、心衰、心律失常、胸腔积液等症状， MM淀粉样变多为AL蛋白沉积，而有心肌严重受损者很少为AA蛋白沉积所致,结缔组织病继发性淀粉样变,以类风湿关节炎(RA)最常见， 发生率已降至5%(3)。 国内尚未见报道。 86年至今国外报道SS继发淀粉样变共有8例，累及肺、皮肤及皮下组织，,鉴别诊断,1 慢性支气管炎 2 支
9、气管扩张 咯血病人 3 支气管内膜结核 4 慢性间质性肺病 弥漫性淀粉样变 5 复发性多软骨炎 韦格氏肉芽肿,治疗和预后,本病为慢性进行性预后不佳。以弥漫性肺实质淀粉样变为严重。平均存活16月。 多死于大咯血，呼衰，感染，全身衰竭 无治疗,例1,例1,例1,例2,例3多结节,例4孤立结节,例5,病生Inheritance Pattern,Finnish type amyloidosis is an autosomal dominant inherited disease.,Mechanism of the Disease Process,Amyloid deposits originate f
10、rom serum precursor proteins. In hereditary forms of the disease, genetically altered forms of serum precursor proteins are responsible for amyloidogenic depositions. In Finnish type amyloidosis, gelsolin serves as the precursor protein.,Mutations Causing the Disorder,A mutant form of gelsolin cause
11、s the amyloidogenic deposition in persons suffering from Finnish type amyloidosis. The mutant gelsolin is caused by a single base mutation in the GSN gene. The transformation of G654 to A654 at residue 187, results in an asparagine or tyrosine substitution for the normal aspartic acid.,How Mutation
12、at Asp187 causes FAF,(A) Red region is S1. Yellow and cyan regions comprise the F-actin binding site of S2. Cyan and orange regions comprise PIP2 (inhibitor of F-actin binding) binding site. (B) Asp187 is within binding distance with three residues and these forces stabilize the local region. When A
13、sp187 is mutated, a trypsin-like protease site at Arg172-Ala173 is likely to be cut.,Chromosome Location of the Disorder,The mutation for Finnish type amyloidosis is located on chromosome 9q34.,DNA Sequence,The nucleotide sequence of the mRNA coding for the protein gelsolin (GSN gene) is: 551 a 750 c 804 g 497 t,