免疫球蛋白轻链型淀粉样变性治疗进展

免疫球蛋白轻链型淀粉样变性(AL)是最为常见的淀粉样变性类型.近年,AL型淀粉样变性的治疗已取得一定进展.笔者拟就AL型淀粉样变性治疗的相关研究进展,包括基于自体造血干细胞移植治疗方案、基于美法仑治疗方案、基于蛋白酶体抑制剂治疗方案、基于免疫调节剂治疗方案及免疫治疗方案进行综述.     

免疫球蛋白轻链型淀粉样变性的诊疗进展

免疫球蛋白轻链型淀粉样变性(AL)为最常见的系统性淀粉样变性,其特征为单克隆免疫球蛋白轻链的错误折叠引起的淀粉样蛋白的沉积.AL发病机制与多发性骨髓瘤(MM)相关,可继发于MM.目前,诊断延误仍然为影响AL疗效的最主要因素.因此,早期诊断及治疗对改善AL患者的预后具有重要意义.笔者拟就AL诊断、治疗及预后进行综述.     

系统性轻链型淀粉样变性细胞遗传学异常检测分析

目的研究系统性轻链型(AL)淀粉样变性患者的细胞遗传学特征。方法收集初诊系统性AL淀粉样变性患者24例和多发性骨髓瘤(MM)患者135例,通过CD138磁珠分选(MACS)结合间期荧光原位杂交(FISH)技术检测系统性AL淀粉样变性和MM患者的细胞遗传学异常,比较二者细胞遗传学异常差异。分析系统性AL淀粉样变性FISH异常与血清游离轻链(sFLC)、N端脑钠肽前体(NT-proBNP)、B型脑钠肽前体(proBNP)、血清肌钙蛋白(cTnT和cTnI)及器官累及之间的关系。结果系统性AL淀粉样变性细胞遗传学异常阳性率为62.5%,其中14q32异位、t(11;14)和+1q21发生率较高,分别为41.7%、37.5%和29.2%。系统性AL淀粉样变性细胞遗传学异常总阳性率、del(13/13q14)缺失率及并存大于或等于3种遗传学异常的发生率均显著低于MM患者,差异有统计学意义(P0.05),而t(11;14)发生率显著高于MM,差异有统计学意义(P0.05)。系统性AL淀粉样变性细胞遗传学异常与临床相关检测指标及器官累及无显著关系(P0.05)。结论 MACS-FISH可用于检测系统性AL淀粉样变性患者的细胞遗传学异常。系统性AL淀粉样变性患者14q32异位、t(11;14)、+1q21有较高的发生率,t(11;14)发生率显著高于MM患者,而并存大于或等于3种细胞遗传学异常和del(13/13q14)发生率显著低于MM患者。     

系统性轻链型淀粉样变性患者心理痛苦现状及其影响因素

目的 了解系统性轻链（AL）型淀粉样变性患者心理痛苦现状,并分析其影响因素。方法 采用方便抽样法,选择2022年3-5月就诊于我院细胞治疗中心的42例AL型淀粉样变性患者,采用一般资料调查问卷和心理痛苦筛查量表包括心理温度计（DT）及问题列表（PL）进行心理痛苦现状调查,并分析其影响因素。结果 AL型淀粉样变性患者心理痛苦得分为（4.57±1.85）分,具有临床意义的心理痛苦检出率达64.2%（DT≥4分）。单因素分析显示：不同性别、婚姻状况、宗教信仰、家庭人均月收入、受累器官数量及是否心脏受累对患者心理痛苦水平有显著影响（0.05）,其心理问题主要体现担忧（97.6%）、经济（71.4%）,疲乏（64.3%）及水肿（54.8%）等方面。多元回归分析显示：家庭人均月收入及是否心脏受累是AL型淀粉样变性患者心理痛苦的主要影响因素,解释了总变异的67.6%。结论 AL型淀粉样变性患者心理痛苦水平较高,临床应重点关注家庭人均月收入低及心脏受累的患者,并根据PL,采取针对性干预措施,提高心理护理质量。     

硼替佐米联合地塞米松治疗原发性系统性淀粉样变性

目的 观察硼替佐米联合地塞米松治疗原发性系统性(AL)淀粉样变性患者的疗效和不良反应.方法 11例AL淀粉样变性患者中明确淀粉样物质者10例:κ型1例,λ型9例.免疫固定电泳阳性者5例:IgG κ型1例,IgGλ型3例,IgAλ型1例.累及肾脏、肝脏、心脏、肠道中2个或以上脏器者10例.11例患者中初治者7例,难治者4例.采用硼替佐米联合地塞米松方案治疗.结果 8例可评价疗效患者,中位疗程3(1～6)个.中位随访时间6个月.器官功能改善者6例,中位起效时间2个月.3例病情进展,2例死亡.常见的不良反应有腹泻、血小板减少、周围神经病变、乏力、带状疱疹等.7例因不良反应减少了硼替佐米剂量,其中2例最终中断治疗.3例未完成1个疗程治疗,发生了癫痫、麻痹性肠梗阻、左心功能衰竭、直立性低血压等严重不良反应.结论 硼替佐米治疗AL淀粉样变性有效,不良反应发生率高,部分较严重.     

肾淀粉样变性病临床病理研究

淀粉样变性病是一种由淀粉样物质在组织内沉积引起的全身性疾病,肾淀粉样变性病是淀粉样物质在肾组织广泛沉积引起的一种少见病,约占全部肾活检的0.21%-1.0%,最终导致肾功能衰竭[1,2]。肾淀粉样变性病一般可分为AL型(轻链蛋白型)和AA型(淀粉样蛋白A型),以AL型居多。目前国内对本病的报道较少。     

高危AL型心脏淀粉样变性行自体外周血干细胞移植的护理干预

目的：总结高危AL型心脏淀粉样变性(CA)患者行自体外周血干细胞移植的护理经验。方法：将2012年梅奥分期应用于系统性轻链型淀粉样变性(AL)行自体外周血干细胞移植(AHSCT)患者评估中,帮助早期正确识别高危CA患者,根据围术期不同阶段心脏风险,实施个体化干预措施,重视患者心理危机干预,细化PICC置管及药浴流程,改进预处理及回输方式,加强粒缺期心衰、心律失常等心脏并发症的管理等。结果：患者均移植成功,术后门诊随访1年,均存活,血液学完全缓解(CR)11例,理想的部分缓解(VGPR)1例,部分缓解(PR)2例；心脏缓解10例,效果良好。结论：梅奥分期应用于高危AL型心脏淀粉样变性行自体外周血干细胞移植护理评估中,有利于早期识别高危风险,采取个体化干预措施,减少移植心脏并发症,改善预后。     

一例以周围神经病变为首要表现的原发性系统性淀粉样变性患者的护理

系统性淀粉样变性（Systemic amyloidosis）是以不可溶性淀粉样蛋白异常沉积于体内各组织器官并导致其功能障碍的少见疾病。临床上可分为原发性、继发性及家族遗传性系统性淀粉样变性等几种类型,其中以原发性系统性淀粉样变性、亦称AL淀粉样变性（Light-chain amyloidosis）最为常见,约占所有淀粉样变性的70%以上。     

检测骨髓异常浆细胞有助于诊断原发性系统性轻链淀粉样变性

原发性系统性轻链淀粉样变性(AL)是系统性淀粉样变性疾病中最常见的类型,最近已明确AL是异常浆细胞导致的恶性肿瘤。这些浆细胞产生过量的免疫球蛋白轻链,形成具有蛋白质毒性的纤维状淀粉样物,通过异常折叠和沉积于多种组织器官,引起多脏器损害。AL诊断较困难,以往主要通过活检组织的刚果红染色。现在使用流式细胞术可以通过患者骨髓浆细胞的免疫球蛋白轻链限制性及异常表型特征检测异常浆细胞克隆,有助于早期确诊AL,并作为诊断AL后临床疗效监测的重要指标。本文就AL的诊断和分型、临床特点、骨髓浆细胞免疫表型的流式细胞术检测,异常浆细胞免疫球蛋白轻链限制性和表型特点等作一简要的综述。     

压力-应变环评估轻链型淀粉样变性患者左心室收缩功能

目的:探讨左室压力-应变环(pressure-strain loop,PSL)定量评估轻链型淀粉样变性(light-chain amyloidosis,AL)患者左室收缩功能改变。方法:选取2018年1月至2020年12月在郑州大学附属肿瘤医院临床确诊的AL患者46例,根据舒张末期室间隔与左室后壁厚度是否>12 mm分...     

Clinical Features and Treatment Response of Light Chain (AL) Amyloidosis Diagnosed in Patients With Previous Diagnosis of Multiple Myeloma

OBJECTIVE: To identify and assess the clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma (MM).PATIENTS AND METHODS: From a prospectively maintained database, we identified 47 patients seen between January 1, 1990, and August 31, 2008, with a diagnosis of AL amyloidosis that was made at least 6 months after MM diagnosis; these patients form the study group.RESULTS: Among the 47 patients, 36 developed typical features, 3 had atypical features, and 8 had an incidental finding of amyloidosis. Amyloid deposits were demonstrated in bone marrow, subcutaneous fat aspirate, or organ biopsy in 24, 19, and 12 patients, respectively. One organ was involved in 29 patients (62%), whereas 11 patients (23%) had involvement in more than one organ. At diagnosis of AL amyloidosis, treatment was changed or started in 22 patients, whereas the same treatment was continued in 21 patients, and no treatment data were available for the rest. The best hematologic response included partial response or better in 11 patients (23%) and stable disease in 18 patients (38%). Improvement in an organ was seen in 3 of the 21 evaluable patients. The median overall survival from diagnosis of AL amyloidosis was 9.1 months (95% confidence interval, 4-14). Of the 6 patients still alive, 2 underwent peripheral blood stem cell transplant, and none had cardiac involvement or involvement in more than one organ.CONCLUSION: Delayed onset of AL amyloidosis is rarely seen in patients with MM and requires a high index of suspicion for prompt diagnosis. Outcome of these patients is poor, especially in the presence of cardiac involvement.AL = light chain; BM = bone marrow; CI = confidence interval; CR = complete response; FA = fat aspirate; HDT = high-dose therapy; MM = multiple myeloma; OS = overall survival; PBSCT = peripheral blood stem cell transplant; PR = partial response; SD = stable disease; VGPR = very good partial responseImmunoglobulin light chain (AL) amyloidosis is a relatively uncommon disorder characterized by the deposition of monoclonal Ig light chains as insoluble and aggregated amyloid fibrils in various tissues, leading to progressive organ dysfunction and death. Both multiple myeloma (MM) and AL amyloidosis are incurable clonal plasma cell proliferative disorders; they are part of a group of disorders termed monoclonal gammopathies, which includes monoclonal gammopathy of undetermined significance and Waldenström macroglobulinemia, among others. Monoclonal gammopathy of undetermined significance, the most commonly diagnosed monoclonal gammopathy, affects more than 3% of the population older than 50 years¹ and has the potential to progress to MM or AL amyloidosis, albeit at a low rate of 1% per year.² Although AL amyloidosis and MM have distinct clinical presentations, patients may present with findings suggestive of both disorders simultaneously. In addition, patients may present with features of MM or AL amyloidosis and subsequently develop features suggestive of the other.The “progression” of AL amyloidosis to MM or development of frank MM in a patient with AL amyloidosis is not seen commonly, probably because of the shorter survival of patients with AL amyloidosis. In one series of 1596 patients diagnosed as having AL amyloidosis during a period of 35 years, only 6 had progression to MM.³ In contrast, a diagnosis of AL amyloidosis is made more frequently in a patient with a preexisting diagnosis of MM. Some reports suggest that 10% to 15% of patients with MM may develop overt AL amyloidosis during the course of their disease, and up to 38% of patients with MM may have clinically occult AL amyloid deposits.^3,4 We designed the current study to identify and describe the clinical features, diagnosis, treatment patterns and response, and outcome among patients who were diagnosed as having AL amyloidosis subsequent to a diagnosis of MM. We describe 47 patients with a histologic diagnosis of AL amyloidosis, made at least 6 months after the initial diagnosis of MM, thus excluding patients with symptomatic AL amyloidosis at the time of the diagnosis of MM.     

Curative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen alpha-chain variant in an English family

A 53-year-old English woman who had been thought to have systemic monoclonal immunoglobulin light chain (AL) amyloidosis was investigated further because of her unusually long 17-year history and a suggestion of renal disease in the family. She was found to have the Glu526Val fibrinogen alpha-chain variant that causes autosomal dominant hereditary systemic amyloidosis. This has not previously been described in a British family. The mutant gene was associated with the same haplotype as in all other reported cases, suggesting a common founder. The patient had already received a renal transplant, but the graft failed within 6 years due to amyloid deposition. Progressive hepatic amyloidosis eventually caused liver failure, although the function of other organs was well preserved. She therefore received hepatic and renal transplants to replace the failed organs and the hepatic source of the amyloidogenic variant fibrinogen. Three years later she is completely well and has no amyloid deposits identifiable by serum amyloid P component scintigraphy. This is the first detailed report of hepatic transplantation for liver failure caused by amyloidosis of any type. The substantial follow-up suggests that fibrinogen alpha-chain amyloidosis is one of the inherited metabolic diseases that can be cured by liver transplantation. The mutation underlying Glu526Val fibrinogen alpha-chain amyloidosis is incompletely penetrant and has a variable phenotype that can clinically mimic AL amyloidosis. Hereditary fibrinogen amyloidosis may be more prevalent than previously suspected and, since AL amyloid is sometimes a diagnosis of exclusion, genotyping for other amyloidogenic proteins is mandatory in all cases in which the amyloid fibrils cannot be positively identified as AL.     

Influence of tissue fixation on the microextraction and identification of amyloid proteins

In surgical pathology, correct immunohistochemical identification of AL amyloidosis poses a particular problem. Immunostaining for lambda- or kappa-light chains is commonly encountered even in non-immunoglobulin-derived amyloidoses, which leads to a false-positive classification as AL amyloidosis. In this respect, microextraction of amyloid proteins from surgical pathology specimens and their subsequent biochemical characterization may prove useful in reaching the correct diagnosis. In this study, we investigated systematically the influence of fixation on the extraction of amyloid proteins from amyloid-containing tissue samples. Tissue samples were obtained from a patient with generalized AA amyloidosis and from a second patient with generalized AL amyloidosis. The samples were stored either unfixed or fixed in phosphate buffered 4% p-formaldehyde, methacarn, or Bouin for 3 days, 1 week, or 1 month. Thereafter, proteins were extracted according to the procedure of Layfield et al, separated by SDS-PAGE and subjected to Western blotting, using antibodies directed against AA amyloid and immunoglobulin-derived lambda-light chain. Following this procedure, a variety of differently sized AA amyloid or lambda-light chain immunoreactive protein bands were found in both patients, which is typical for amyloid proteins. Fixation time did not per se prohibit the extraction of these amyloid proteins from tissue samples, which remained detectable irrespective of fixation time. Although all three fixatives impaired the resolution of some, but not all, individual amyloid proteins, this procedure may help to confirm or reject a diagnosis of AL amyloidosis, because detection of several lambda- or kappa-light chain immunoreactive protein bands in the low-molecular-weight range (<20 kDa) is a common characteristic of their amyloid nature.     

Incidence of AL Amyloidosis in Olmsted County,Minnesota, 1990 through 2015

Objective

To determine the incidence of immunoglobulin light chain amyloidosis (AL amyloidosis) in a strictly defined geographic area from 1990 through 2015.

中老年人心肌淀粉样变性4例临床及其CMR表现

目的回顾性分析4例中老年心肌淀粉样变性的临床资料以及心脏磁共振成像特点,以提高诊断水平。材料与方法分析2010年8月至2016年12月在北京医院诊治并经病理证实的心肌淀粉样变性中老年患者4例,总结患者性别、年龄、临床表现、心脏核磁共振(cardiovascular magnetic resonance,CMR)影像特点和病理特点、治疗方式。结果患者平均年龄约68岁(57~72岁),病程较长(9~36个月),4例均出现血清N末端B型利钠肽原、肌钙蛋白增高并表现为不同程度的左心室收缩功能障碍,3例心律失常,2例低电压及病理Q波,3例血尿轻链水平增高。超声心动图4例可见心肌增厚,室间隔为著,诊断为非梗阻性肥厚性心肌病。CMR显示左心室心肌非对称性增厚,心肌质量明显增加,但心腔无扩大,心肌运动减低,3例收缩功能减低,左心室心肌呈弥漫心内膜下或透壁延迟强化,心腔暗血池及心肌较心腔提前抑制。4例经病理证实为原发性系统性淀粉样变性轻链型(AL型),3例通过心外组织活检、1例尸检,其心脏外受累主要表现为肾、肝、肠道、周围神经、皮肤。1例应用硼替佐米加地塞米松、马法兰加地塞米松方案化疗,无心脏不良事件发生;2例明确诊断但放弃治疗;1例明确诊断较晚,且未进行有效治疗,死亡。结论心肌淀粉样变性的心脏磁共振成像主要表现为心肌肥厚、心肌质量增加,增强扫描后心肌较心腔提前抑制,心腔呈暗血池,心肌延迟强化的特征表现为弥漫透壁或心内膜下强化,可提示临床难治性心衰的病因诊断,在诊断及鉴别诊断中起重要作用。     

Holter Monitoring in AL Amyloidosis: Prognostic Implications

PALLADINI, G., et al. : Holter Monitoring in AL Amyloidosis: Prognostic Implications. The heart is involved in more than one third of patients with primary (AL) amyloidosis at diagnosis and it is by far the most common cause of death. Rhythm and conduction abnormalities generally represent the terminal event. The aims of this study were to determine the spectrum of Holter abnormalities found in AL amyloidosis and to assess their prognostic significance, particularly in relation to sudden death. Fifty-one patients with AL amyloidosis were included, and all of them had a complete history, physical examination, two-dimensional echocardiography, and 24-hour Holter monitoring. Fifty-five percent of these patients had echographic signs of heart involvement and 23% had heart failure. Complex ventricular arrhythmias were found in 57% of patients, couplets in 29%, and nonsustained ventricular tachycardia in 18%. Overall median survival was 23.4 months. Congestive heart failure, echocardiographic abnormalities, and Holter abnormalities adversely affected survival. The multivariate analysis demonstrated that interventricular septum thickness and couplets were independent predictors of survival. The presence of couplets correlated with sudden death. Holter monitoring may contribute to assessing the prognosis of patients with AL amyloidosis.     

Leukocyte chemotactic factor 2–related amyloidosis presenting with severe jaundice and hepatic encephalopathy

Amyloidosis is a well‐known disease with various types and subtypes. One of the most recently identified types is leukocyte chemotactic factor 2 amyloidosis (LECT 2), which was found to be common in certain ethnic backgrounds. It is suggested that the diagnosis of this type is vital to prevent any therapy‐related complications when it is erroneously diagnosed as AL amyloidosis. The clinical presentation is usually slowly progressive kidney disease and mild hepatic impairment. We report a case of LECT2 amyloidosis, which presented with severe painless cholestasis and hepatic encephalopathy alongside progressive kidney disease.     

Paraneoplastic kidney lesions

The authors summed up the results of a study of paraneoplastic nephropathy combined with a tumor process of different sites in 41 patients treated over a 14-year period. Data on the frequency of the combination of a tumor with nephropathy, the time of tumor diagnosis from the appearance of the signs of renal involvement, the frequency of various morphological changes in the kidneys (amyloidosis, nephropathy of glomerulonephritis type) were correlated with the literature data. The importance of the knowledge of clinical features, a course of nephropathy for early recognition of tumors and correct therapeutic tactics was discussed.