淀粉样变性 amyloidosis 2014-02-25

淀粉样变性amyloidosis 由于蛋白折叠异常而导致不可溶的纤维性淀粉样物质沉积于器官或组织的细胞外区所引起的一组疾病。 淀粉样物质-因其接触碘与硫酸 时出现与淀粉相似的反应而得名。

淀粉样物质的形成 在特殊环境中,错误折叠,重新经历生理性折叠途径的部分程序，生成错构分子,从而发生自我聚集,形成淀粉样物质局部沉积。其中,寡聚体,或初原纤维,可以通过促进靶组织细胞的凋亡介导细胞毒性。

淀粉样物质构成 淀粉样的蛋白纤维（淀粉样多肽）这是组成淀粉样物质的主体，是相应的前体蛋白部分水解断裂的片断，作为单体参与形成多聚化β－片层结构。 淀粉样物质附加成分 血清淀粉样P成分( serum amyloid P　component, SAP ) 是一种糖蛋白, 在钙离子存在的情况下,能通过特殊模序和淀粉样物质共有构象结合,抵制相应酶的蛋白水解作用,保护淀粉样物质

糖胺聚糖( glycosaminoglycans,GAGs)：GAGs是由二糖(糖醛酸/己糖胺)单位重复聚合形成的多糖链,可以和蛋白质核心共价结合，与淀粉样变密切相关。 载脂蛋白E：是一种富含精氨酸的碱性蛋白,可能通过发挥病态分子伴侣(pathological chaperone)的作用,参与淀粉样物质的沉积。

1.血清蛋白醋酸纤维膜电泳，即蛋白电泳：M蛋白在α2—γ区形成浓密区带， 从扫描图中可见基底较窄、高而尖锐的蛋白峰。在γ区， 蛋白峰的高与宽之比>2：1;在β区和α2区>1：1。

淀粉样变性分型

继发性肾淀粉样变病因 常有慢性破坏性炎症性的前驱病灶如： ①慢性空洞型肺结核、 ②慢性化脓性骨髓炎、 ③类风湿关节炎、 ④慢性支气管扩张症、 ⑤肺脓肿、 ⑥Ⅲ期梅毒等, 去除前驱性病灶是治疗继发性淀粉样变的关键

鉴别 原发继发 原发性不受高锰酸钾氧化的影响,刚果红染色仍为砖红色; 继发性经高锰酸钾氧化后,刚果红染色则转为阴性。

AL型淀粉样变性病是异常的轻链蛋白和少数重链蛋白沉积造成的，部分病例可发现多发性骨髓瘤等单克隆免疫球蛋白异常沉积。 血清淀粉样相关蛋白降解产物组成的淀粉样蛋白A型(AA型) (见于继发性淀粉样变和部分家族性淀粉样变)

肉眼：粉红或灰白石蜡样增加肾脏体积的慢性肾脏疾病皮质有灰白色淀粉样沉积物

普通光镜：心肌纤维之间有不定形的浅红色沉淀物 淀粉样蛋白的特征

刚果红染色:淀粉样物质经染色后应为橙红色，偏振光下，淀粉样物质为“苹果绿”双折射

免疫荧光： κ轻链蛋白阳性,λ轻链蛋白阳性 免疫电镜检测免疫电镜可见显示轻链沉积的胶体金颗粒特异定位于淀粉样纤维部位,每个病例均被单一品种轻链蛋白(κ或λ) 标记 电镜：纤细、不分枝、僵直的纤维

病理机制 主要有以下三种方式损伤组织和器官 ①物理方式 ②细胞毒作用 ③诱导细胞凋亡

肾淀粉样变 在肾脏病中,相对少见,一般占全部肾活检患者的0.5% ～1.0% 临床特点是:中老年起病,多表现为肾病综合征,血尿不突出,治疗反应差,易发展为肾功能不全以及多系统受累(如巨舌、皮疹、肝脾大、胃肠道功能异常、心肌肥厚、低血压等) 。 其中绝大多数为原发性淀粉样变性病，即轻链蛋白沉积型（AL）所形成。

AL 是最常见也是预后最差的淀粉样变性,患者平均存活期12～15 个月。伴有MM或出现心衰、肾衰、黄疸者预后不良,存活期< 6 个月。 治疗侧重于抑制B 细胞增殖,最佳方案为MP (马法兰+ DXM) ,有效率50 % , VAD(长春新硷+ 阿霉素+ 地塞米松) 大剂量马法兰+PBST(自体外周血造血干细胞移植) 有效率可达85 %。 新型蒽环类抗生素I－DOX疗效可能更佳,干扰素仅对骨髓瘤所致的AL 有效 沙利度胺+DXM

心脏淀粉样变性(Cardiac Amyloidosis) 指淀粉样物质在心肌内沉积，临床上常表现为限制性心肌病/难治性心力衰竭，伴或不伴各种类型传导阻滞。心脏淀粉样变性多见于各种系统性淀粉样变性。 免疫球蛋白轻链AL （Aκ Aλ ）导致的原发性淀粉样变性 transthyretin(ATTR)相关的遗传性淀粉样变性（突变型TTR） 老年性系统性淀粉样变性SSA（野生型TTR）

ATTR型 遗传性淀粉样变性：常染色体显性遗传，最常见致病基因为transthyretin (TTR)，已发现100多种突变，生成淀粉样物质前体TTR变异体。其他突变蛋白包括纤维蛋白素原Aa、溶菌酶、载脂蛋白A-1和肌动蛋白。 通常表现有周围神经病变、自主神经功能障碍（ 胃肠道症状）、肾脏损害、心肌病。肾脏和心脏损害较AL淀粉样变性少见，预后也较好。临床表现因突变不同而不同。 Val30Met型：有多种心脏传导异常，常需要安装起搏器，但很少发生心力衰竭。生存率80%。 TTR 主要由肝脏产生，因此肝脏移植成为其最重要和有效的治疗方法，可改善患者预后。

SSA型 本型与年龄相关：＞80岁约10%，＞90岁约50% 主要沉积于心脏与腕管，室壁增厚明显，是由正常转运甲状腺蛋白沉积所致。 最近学者发现淀粉样物质的沉积于心肌细胞基底膜密切相关。在基底膜上硫酸肝素或其他分子与甲状腺素转运蛋白相互作用，使其在心脏沉积。 99mTc-DPD闪烁扫描特异性诊断。 SSA心脏受累患者预后较好，即使有心力衰竭，平均生存时间仍近5年。导致的心力衰竭对药物治疗的反应比其他型淀粉样变性好。

病生理 由于淀粉样物质浸润并在间质沉积，导致细胞代谢、钙离子转运、受体调节的改变和细胞水肿。 *早期为心脏舒张功能障碍以后发展到限制性心肌 病，发展为难治性充血性心力衰竭； *如果影响到心脏传导系统可导致多种难治性心律失常，最常见的是传导阻滞和心房纤颤，严重时需安装临时起搏器。 *肺血管淀粉样变导致肺动脉高压和肺心病。

临床表现 1）早期为心脏舒张功能障碍： 2）限制性心肌病右心衰竭的症状和体征：颈静脉压增高、右室奔马律、肝脏肿大和外周水肿。部分患者发展为难治性充血性心力衰竭。 3）难治性心律失常 4）肺动脉高压和肺心病 5)特征性心电图：标准肢体导联低电压、胸前导联R波递增不良（类似于前间壁心肌梗死恢复期波形）、常伴有房颤和传导阻滞。

6）特征性超声心动图： 心室壁和室间隔明显 对称性肥厚，左室心腔正常或缩小，左室舒张 功能减退；合并有心肌特征性回声增强（颗粒 状闪烁样表现）；此外还可有心房扩大；瓣膜增厚或反 流；心包积液；晚期有充盈压增高的限制性表现。 7）心肌锝99m焦磷酸盐（Tc-99m-PYP）闪烁照相表 现为同位素浓集阳性影像，因锝99m焦磷酸盐可以结合 到与淀粉样纤维相关的钙分子上。 其他：原发病的表现

心脏淀粉样变性确定诊断的依据 1、超声心动图心室壁和室间隔明显对称性肥 厚，左室心腔正常或缩 小，左室舒张功能 减退，而血压不高者；心肌回声增强（颗粒样闪 烁），对于心脏淀粉样变性诊断的特异性达100％； 2、心电图QRS波低电压，与心室壁增厚相结合，即可诊断心脏淀粉样 变性，因为其他原因导致的左心室肥厚QRS波为高电压。 3、病理确诊： 以往认为证实淀粉样物质在活检组织中沉积是心脏淀粉 样变性的唯一方法。心内膜活检是心脏淀粉样变性最直接的确诊方 法。但如果在心脏以外活检发现淀粉样物质沉积，结合超声心动图 特征性改变，也可诊断，无需再做心内膜活检。这些部位包括舌头、 皮 下脂肪垫、肾脏、骨髓、胃粘膜，直肠粘膜等。皮下脂肪垫活检结合骨髓刚果红染色对淀粉样变性患者组织学诊断率达90 ％。 确定淀粉样物质沉积可用HE、龙胆紫、结晶紫和硫磺素染色，但刚果红染色在偏光下产生苹果绿样折射是淀粉样变性最特异的染色。也可在电子显微镜下观察淀粉样物质沉积。

心脏淀粉样变性治疗 心脏淀粉样变性治疗包括基础病治疗和心脏对症治疗。基础病治疗根据淀粉样物质产生和类型而采用化疗、自 体干细胞移植和心肝联合移植等，均能改善患者预后。心脏对症治疗只缓解症状，并不能明显改善预后。 1、对于限制性心肌病舒张功能障碍，右心衰竭患者可小心应用ACEI，长效硝酸盐，其他血管扩张剂和利尿剂。 2、钙离子拮抗剂和β受体阻滞剂由于负性肌力作用而慎用。地高辛通过淀粉样纤维与细胞外膜结合，敏感性和毒性增加，应应禁用或慎用。 3、胺碘酮可治疗心房纤颤，对有症状的心动过缓和高度传导阻止，应安装起搏器治疗。

Cardiac amyloidosis : Updates in diagnosis and management Archives of Cardiovascular Disease (2013) 106, 528—540

The organs involved are typically the liver, kidney, gastrointestinal tract, nervous tissue and heart. Cardiac involvement may occur in the three main types of amyloidosis (AL,ATTR,SSA) and has a major impact on prognosis. AL:50% have CA CA:70%is AL In secondary amyloidosis, cadiac involvement is rare or minimal or clinically non-significant ． .

Electrocardiography Transthoracic echocardiography Cardiac magnetic resonance imaging cMRI）better characterizes myocardial involvement, functional abnormalities and amyloid deposition due to its high spatial resolution. Nuclear imaging has a role in the diagnosis of SSA Cardiac biomarkers

SSA have better prognosis than LA SSA have better prognosis than LA. Cardiac treatment of heart failure is usually ineffective and is often poorly tolerated because of its hypotensive and bradycardiac effects .

Light-chain amyloidosis AL reported incidence ： 8.9per million person-years 　　　ＵＳＡ roughly500 patients per year　　France lambda ＞ kappa LCs A serum and/or　urine monoclonal component is detectable 80—90% of patients Plasmocytosis is present in the bone　marrow in > 50% of patients

diagnosis echocardiography Histological　finding Congo red positive deposits,which display characteristic dichroism and apple green birefringence under polarized light． Electron microscopy may be useful to confirm the presence of amyloid deposits,which typically display the ultrastructural appearance of　randomly arranged fibrils ，7—10 nm in external diameter. Immunohistological typing is indispensable to make the differential diagnosis between different types of amyloid disease echocardiography

Diagnostic criteria for cardiac involvement wall thickness in end-ventricular diastole　of ≥ 12 mm NT-proBNP) to > 332 ng/L (in absence of renal failure) 2010 meeting of the International Society of Amyloidosis in Rome

current staging system the Mayo Clinic staging 　based on NT-proBNP (cut-off　value = 332 ng/L; BNP = 100 ng/L) and cardiac troponin (cut-off value = 0.035 ｕg/L), 　three groups high risk (stage III: both biomarkers are increased)　 intermediate risk (stage II: at least one biomarker is abovethe cut-off value) low risk (stage I: both biomarkers are below the cut-off　values).

Another biomarker — midregional proadrenomedullin（肾上腺髓质前体素中段） which is produced by many organs, including the heart —was tested in an Italian study in 2011 , in 130 patients with confirmed de novoAL. The authors found that a high concentration of mr-PAM was associated with a higher early mortality rate of 40% at 6 months，when its value was > 0.75 nmol/L.

Electric disturbances(90 %） Low voltage QRS complex (defined as all limb leads < 0.5 mv) 50% a pseudoinfarct pattern on the precordial. conduction abnormalities 　　　AF15% 　　　second and third degree AVCB 　　　VT 5% a fragmented QRS (notches and RsR’ pattern　in the absence of QRS prolongation) was more　frequent in patients CA． higher mortality rate compared with the‘normal’ QRS group , not spe-cific ．

Holter Complex ventricular arrhythmias have been reported to be prognostic determinants for survival, but only couplets correlated with　sudden cardiac death and were independent predictors　of survival． HV prolongation　may be a marker of significant infiltration of myocardium　by amyloid fibrils, which may be responsible not only for VT, but also for high degree AVCB or asystole

Echocardiographical findings Transthoracic echocardiography (TTE) •increased LV wall thickness ≥ 12 mm with ‘brilliant’ speckled appearance of the myocardium ；mean LV wall thickness > 15 mm was independently associated with worse outcome •normal or small LV cavity; •preserved LV ejection fraction (LVEF) > 50% (early stage), but reduced S and E’ waves at the basal, septal or lateral myocardium level, reflecting the poor longitudinal function and altered LV relaxation; •abnormal mitral filling pattern, due to mild or moderate LV diastolic dysfunction at a later stage, a typical severe restrictive mitral filling pattern with E/A ratio > 2,increased E/E’ and small A wave due to atrial dysfunction; •the elevated LV filling pressure may lead progressively to left atrial enlargement (diameter > 23mm )

•right atrial enlargement and dilated vena cave reflecting right ventricular (RV) filling pressure; •increased interatrial septal thickness •increased RV free wall thickness (> 7 mm) with RV systolicand diastolic dysfunctions associated with worse survival •left and right valve thickening, usually responsible for mild regurgitation; •reduced aortic ejection time (< 273 ms） •small pericardial effusion in 50% of cases atrial thrombi AL patients were younger and had less atrial fibrillation than those with other types of amyloidosis; however, the AL group had significantly more intracardiac thrombi and more fatal embolic events

Diagnostic and prognostic value of newechocardiographical techniques longitudinal strain (LS) and 2D global LS (2D-GLS) provided incremental value over NT-proBNP, cardiac troponin and all other clinical variables assessed． two-dimensional speckle-tracking imaging in differentiating cardiac amyloidosis from other causes of LV hypertrophy－－reduced basal strain and regional variations in LS from base to apex and that a relative ‘apical sparing’ (average apical LS/[average basal LS + mid-LS])

Cardiac magnetic resonance imaging cMRI sensitive for detecting the presence of infiltrative cardiomyopathy, even in cases of normal LV wall thickness. useful for tissue characterization of the myocardium by showing different patterns: transmural late gadolinium enhancement (LGE) or, more typically, a large diffuse annular LGE;

T1 mapping may have greater ability to predict outcome than LGE cMRI may offer promise for the early detection of cardiac involvement using LGE, but this has yet to be proved

Nuclear imaging 99mTc-aprotinin(抑肽酶） 99mTc-DPD 123ＩSAP(Ca dependent manner) 99mTc-DPD　has been proven to　be very useful in the differential diagnosis of ATTR and AL　aetiologies. In AL,99mTc-DPD uptake is absent or weak． 123Ｉ-metaiodobenzylguaninine scintigraphy （闪烁扫描） cardiac autonomic dysfunction

Cardiac complications CHF chronic elevated LV filling pressure leads to left atrial　enlargement then to paroxysmal or persistent AF， systemic embolic events non-sustained or sustained VT conduction disturbances are more in cardiac ATTR orthostatic hypotensive dysautonomia can cause　syncope ，loss　of heart variability; an SDNN < 50 ms chest pain may occur in rare cases where amyloid　deposits affect the microcoronary circulation

Management and treatment of LA chemotherapy The goal of treatment should be the achievement of a haematological response, which is an important predictor of prolonged survival. 　Impressive efficacy,with > 60% haematological response, has been reported with　melphalan-dexamethasone（马法兰－地米） regimens, with median survival up to 5 years. 　(ASCT) obtains ONLY a similar haematological response rate .

Thalidomide（沙利度胺）, lenalidomide and the proteasome inhibitor　（蛋白酶抑制剂）bortezomib have been used in several studies with　excellent results

Prognosis extension and severity of organ involvement haematological response to therapy. Only 15 years ago－－median overall　survival of 18 months Now survival > 5 years. Early diagnosis is therefore a critical step to avoid irreversible damage, especially to the heart.

Cardiac supportive treatment Most drugs commonly used for the treatment of congestive heart failure are inefficient or appear to be dangerous in patients with AL, ATTR or SSA ． Beta-blockers are deleterious ACEI digitalis （地高辛） Loop diuretics－－ the mainstay of management. Amiodarone （胺碘酮）should be　considered as first-line therapy for arrhythmia. Anticoagulation therapy is mandatory in patients with supraventricul　ararrhythmia Pacemaker　implantation

Hereditary transthyretin-related amyloidosis ATTR ATTR 　liver synthesize. chromosome 18 (18q23). The disease is transmitted as　an autosomal dominant trait（常显） with high penetrance（外显率） neurological sensory-motor peripheral neuropathy and autonomic dysfunction. The motor deficit involves the large sensory and motor nerve fibres. Autonomic dysfunction affects the　cardiocirculatory (orthostatic hypotension), gastrointestinal　and genitourinary systems. Cardiac manifestations －－ arrhythmias、 syncope 、sudden death 、 dyspnoea 、 heart failure

Clinical manifestations and age of onset vary depending on the TTR mutation, sex, parental gene transmission and　geographical。 ECGs, TTE and cMRI of cardiac ATTR show similar to cardiac AL 99mTc-DPD uptake is strong in ATTR amyloidosis, inboth mutant and wild-type ATTR

The diagnosis strategy for ATTR combines pathology and molecular genetic testing. Cardiac medical supportive treatment is limited and is similar to that for AL。 The specific treatment of ATTR is a liver transplant with or without a heart transplant, depending on phenotypic presentation and the age of the patient.

Systemic senile amyloidosis (SSA）wild-type ATTR native TTR　 deposite in the heart. age> 80 years　 around 10% age > 90 years 　50% in some rare cases, TTR deposition in the heart results in an important increase in ventricle walls, mimicking concentric hypertrophic SSA occurred more than 90% in men (aged > 70）

localized in the　heart and the carpal tunnel. characterized by an important　symmetric increase in LV wall thickness (significantly thicker　than that in AL and ATTR). History of myocardial infarction,arrhythmia and/or bundle branch block are present in one　third of patients ． EMB is the only way to definitively diagnose SSA

cardiac therapeutic agents(ACEI, beta-blockers),generally already prescribed for previous myocardial　infarction or hypertension, are better tolerated than in　other types of amyloidosis.

Comparison AL, SSA and ATTR amyloidosisIt is not possible to differentiate AL, ATTR and SSA accurately　 average age at diagnosis was higher in AL than in ATTR;all SSA patients were elderly men; mean LV wall thickness was higher in SSA than in ATTR andAL; LVEF was moderately depressed in SSA but not in AL or ATTR; ATTR patients displayed low QRS voltage less often AL patients had greater haemodynamic impairment. AL was independently associated with worse survival, whereas SSA　predicted freedom from major cardiac events A large longitudinal study that included 233 patients with a clear-cut diagnosis

Clinical implications There are three main questions that the clinician should be aware of: 1. how to detect cardiac amyloidosis; 2.when to thinkabout it; 3. to whom to refer the patient? In fact, a patient with dyspnoea, unexplained fatigue and LV hypertrophy on TTE contrasting with the microvoltage of QRS amplitude should alert the clinician to an infiltrative process rather than a classical sarcomeric hypertrophic or hypertensive cardiomyopathy;

Conclusion Cardiac involvement is difficult to diagnose and treat. Extracardiac signs,unexplained LV thickening on echocardiography in the absence of　increased voltage on ECG, favour amyloid cardiomyopathy.　 The cMRI pattern of LGE　appears to be very characteristic.99mTc-DPD scintigraphy 　is　an promising technique for revealing the cardiac deposits　of ATTR and SSA.　 Unlike other causes of heart failure, supportive treatment is usually very limited and can be dangerous SSA is probably often underdiagnosed but has a betterprognosis than AL and ATTR..