M蛋白相关范可尼综合征:4例临床分析

目的总结并分析北京协和医院近27年收治的M蛋白相关范可尼综合征患者的临床特征和治疗效果,以期提高临床医师对此类疾病的认识。方法采用回顾性分析方法,对北京协和医院1986年1月至2013年5月收治的4例M蛋白相关范可尼综合征患者的临床表现、生化特征、骨骼表现以及治疗效果进行总结。结果 4例患者的病程为3个月³年,均有明显骨痛,无体重下降。实验室检查均符合范可尼综合征诊断,24 h尿轻链KAP和LAM均明显升高,其中3例患者血或尿免疫固定电泳发现M蛋白。4例患者骨髓穿刺和活检病理均提示骨髓浆细胞比例高于正常(2.0%3年,均有明显骨痛,无体重下降。实验室检查均符合范可尼综合征诊断,24 h尿轻链KAP和LAM均明显升高,其中3例患者血或尿免疫固定电泳发现M蛋白。4例患者骨髓穿刺和活检病理均提示骨髓浆细胞比例高于正常(2.0%⁵.5%),均未发现淀粉样变证据。3例行肾穿刺活检结果均提示肾间质病变。治疗方法:补钾、纠酸、补磷、维生素D制剂和钙剂治疗,针对浆细胞增多的化疗作用有限。结论对于成人起病的范可尼综合征、尤其是表现有明显骨痛的患者,应注意筛查M蛋白。对诊断为M蛋白相关范可尼综合征的患者进行长期随诊十分重要。     

Free light chains in plasma of patients with light chain amyloidosis and non-amyloid light chain deposition disease. High proportion and heterogeneity of disulfide-linked monoclonal free light chains as pathogenic features of amyloid disease

Immunoglobulin light chain amyloidosis (AL) and non-amyloid light chain deposition disease (NALCDD) are different forms of protein aggregation disorders accompanied by a monoclonal gammopathy. Monoclonal free light chains (FLCs) are precursors of the pathological light chain tissue deposits that are fibrillar in AL and granular in NALCDD. However, direct biochemical examination of plasma FLC precursors, which would allow comparison and better understanding of these two diseases, is still lacking. In this study, we examined FLCs in plasma of patients with AL and NALCDD by employing separation on Sep-PaK C18 cartridges, micro-preparative electrophoresis, Western blotting and mass spectrometry. Comparative analysis of AL versus NALCDD and control plasma samples showed new evidence of increased level and heterogeneity of circulating disulfide-bound FLC species in AL. In addition to full length monomers comprising the disulfide-linked FLCs, the monoclonal disulfide-bound FLC fragments were typically revealed in AL plasma. We hypothesized that enhanced disulfide binding of FLCs in AL interferes with their normal clearance and metabolism, which in turn might play a role in amyloid formation. The applied methods might be useful to diagnose or predict the pathological form of the disease and shed light on the mechanisms involved in light chain aggregation in tissues.     

轻链沉积病患者临床病理特征

目的:阐明轻链沉积病(LCDD)患者的临床病理特征、预后及其相关危险因素。方法:回顾分析LCDD患者的临床、病理及随访资料,应用Kaplan-Meier法分析肾脏存活率,COX回归模型分析预后危险因素。结果:观察45例LCDD患者,肾活检时平均年龄50.8岁,男∶女1.6∶1。11例(24.4%)患者同时确诊多发性骨髓瘤(MM)。患者高血压、贫血、肾功能不全、尿蛋白定量≥3.5 g/24h和镜下血尿的发生率分别为80.0%、95.6%、95.6%、44.4%和82.2%。血清单克隆免疫球蛋白条带阳性者为26.2%,血清轻链κ/λ1.65者占84.4%,31.1%为显著异常(8),33.3%患者补体C3降低。80%的患者组织学改变为肾小球结节样病变,20%为肾小球轻至中度系膜增生,53.3%患者肾小管间质慢性病变重度,77.8%患者光镜下存在轻链相关动脉病变。免疫荧光提示κ轻链沉积占93.3%,沿肾小管和肾小球基膜线样分布,系膜区团块状分布。5例患者失随访,余40例患者平均随访22.1个月,共26例(65.0%)进入ESRD,平均肾脏存活时间为33.8月。单因素和多因素COX回归分析显示,肾活检时血清肌酐(SCr)、尿视黄醇结合蛋白(RBP)是进展至ESRD的重要危险因素,未发现其他临床及病理指标与肾脏预后相关。结论:LCDD多发于中年男性,临床表现高血压、蛋白尿、肾功能不全、贫血,血清轻链比值异常较血清免疫固定电泳是更为敏感的诊断提示。肾小球结节病变、肾小管基膜增厚,电子致密物沿肾小球基膜内侧缘和肾小管基膜外侧缘沉积是主要病理表现。轻链沉积以κ型为主。LCDD患者预后差,SCr、RBP是影响预后的独立危险因素。     

Immunoglobulin Vlambda light chain gene usage in patients with Sj?gren's syndrome.

OBJECTIVE: To determine whether patients with Sj?gren's syndrome (SS) have abnormalities in Ig Vlambda and Jlambda gene usage, differences in somatic hypermutation, defects in selection, or indications for perturbations of B cell maturation. METHODS: Individual peripheral B cells from SS patients were analyzed for their Vlambda gene usage by single-cell polymerase chain reaction amplification of genomic DNA and compared with those from normal controls. RESULTS: Molecular differences from controls in Vlambda-Jlambda recombination were identified that were reflected by findings in the nonproductive Vlambda repertoire of the patients, including enhanced rearrangement of Vlambda10A and Jlambda2/3 gene segments. In addition, a number of abnormalities in the productive repertoire were identified, indicating disordered selection. A greater usage of 4 Vlambda genes (2A2, 2B2, 2C, and 7A), representing 56% of all productive Vlambda rearrangements, was observed, suggesting positive selection of these genes. Overutilization of Jlambda2/3 and underutilization of Jlambda7 in both nonproductive and productive Vlambda rearrangements of SS patients compared with controls suggested decreased receptor editing in SS. The mutational frequency did not differ from that in controls, and positive selection of mutations into the productive V gene repertoire was found, similar to that in controls, although mutational targeting toward RGYW/WRCY motifs, typically found in controls, was not found in SS patients. CONCLUSION: Disturbed regulation of B cell maturation with abnormal selection, defects in editing Ig receptors, and abnormal mutational targeting may contribute to the emergence of autoimmunity in SS.     

Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis. Clinical features, immunopathology, and molecular analysis

Monoclonal immunoglobulin deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain deposition disease, and as similar but distinct deposits in light and heavy chain deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal immunoglobulin deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce immunoglobulin fragments that are related to those deposited in the affected tissues.     

Serum immunoglobulin free light chain and heavy/light chain measurements in POEMS syndrome

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia. Nearly all patients present with a λ-restricted monoclonal gammopathy. Most patients with POEMS syndrome have been reported to have a normal serum free light chain ratio (sFLC-R), but the underlying mechanism is still unclear. We assessed the serum free light chains in 83 patients with newly diagnosed POEMS syndrome. The clinical and laboratory data associated with this disorder were collected to identify factors affecting sFLC-R. Fifty-six patients (67 %) showed elevated serum free λ light chains, but only 11 patients (13 %) had an abnormal sFLC-R. A comparison of patients with and without abnormal sFLC-Rs indicated that the latter group had more common splenomegaly and worse renal function. However, the introduction of an extended renal range for sFLC-R did not dramatically improve the diagnostic value of sFLC-R in these patients. Further analyses identified a correlation between the serum free κ light chain and the uninvolved immunoglobulin in patients with an IgAλ clone, implying that the activation of polyclonal immunoglobulin production could mask the presumed skewing of the sFLC-R induced by the underlying monoclonal gammopathy. Therefore, a serum heavy/light chain (sHLC) assay was performed in a subset of patients with stored serum samples available, and the prevalence of abnormal sHLC ratios was high in these patients. In summary, the overproduction of polyclonal immunoglobulin accounts for the high frequency of normal sFLC-R in patients with POEMS syndrome. The sHLC assay may provide unique information about this disorder.     

Aortic regurgitation and pigmentation - unusual features of Noonan syndrome.

A patient with typical features of Noonan's syndrome showed aortic regurgitation and widespread diffuse hyperpigmentation, features not previously associated with this syndrome. Detailed endocrine and dermatological studies failed to delineate the cause of hyperpigmentation. In addition to mild aortic regurgitation, cardiac catheterization revealed mild left ventricular dysfunction, probably due to primary myocardial disease. Other interesting findings included lymphedema and sexual infantilism despite normal testosterone levels.     

低分子右旋糖酐导致肾病综合征患者急性肾损伤的临床病理特征及预后

目的:回顾性分析肾病综合征(NS)患者使用低分子右旋糖酐(低右)所致急性肾损伤(AKI)的临床和病理特征,旨在提高对低右相关肾损害的认识。方法:选取2007年4月至2014年6月,南京军区南京总医院肾脏科收治的20例外院诊断NS、使用低右后出现AKI的患者,排除其他药物、感染、尿路梗阻等因素导致的AKI。观察其临床表现、病理特点及预后。结果:(1)一般情况:20例患者中男性17例,女性3例,平均年龄26.70±14.18岁,肾脏病病程4周(3~10周),初发初治16例。起病时血清肌酐(SCr)65.42±17.68μmol/L。均在外院诊断NS后使用低右治疗,通常剂量500 ml/次(2~10次),AKI持续时间4±2.25周,发生AKI后60%患者出现贫血,24h尿蛋白定量和尿沉渣红细胞计数显著增加(P0.05),肾小管功能损伤明显,尿糖阳性率由5%升至55%。(2)肾脏病理:本组患者肾活检诊断足细胞病9例(45%)、局灶节段性肾小球硬化7例(35%)、IgA肾病2例(10%)、膜性肾病1例(5%)、IgM肾病1例(5%)。2例在AKI发生前行肾活检,18例在AKI病情稳定后行肾活检术,16例合并急性肾小管坏死(ATN),2例合并急性间质性肾炎(AIN),15例近端肾小管上皮细胞见大量等立方空泡变性,15例出现肾小管上皮细胞扁平、刷状缘脱落,14例间质有炎症细胞浸润。(3)治疗:10例行连续性肾脏替代治疗,其中3例后续转为腹膜透析。对患者原发病的治疗采用激素且有效者(20%)、激素依赖及抵抗者分别为25%和30%。另有5例患者随访时间不足6个月。(4)预后:5例患者出院时SCr恢复正常,10例随访1月内SCr正常,5例随访3月后肾功能未恢复,最终2例最终进入维持性透析。结论:NS患者使用低右可导致AKI,部分患者长期预后不佳。NS患者应慎用低右扩容。     

Clinicopathologic features and prognostic indicators in Chinese patients with myelofibrosis

Objective: To define the clinicopathologic features, outcome, and prognostic indicators of myelofibrosis (MF) in Asian patients.

Methods: Two hundred and seventy consecutive Chinese patients (primary MF, n?=?207; post-polycythemia vera MF, n?=?27; and post-essential thrombocythemia MF, n?=?36) from seven regional referral hospitals were analyzed.

Results: The median overall survival (OS) for primary MF was 66 months. Multivariate analysis showed that age >65 years (P?=?0.02), platelet count?<100?×?10⁹/l (P?=?0.001), and leukemic transformation (P?=?0.001) negatively impacted on OS. The median OS of 63 patients with secondary MF was 44 months. In primary MF, the 10-year cumulative risk of leukemic transformation was 28%. On multivariate analysis, unfavorable karyotypes significantly predicted inferior leukemia-free survival (LFS) (P?=?0.03). In secondary MF, the 10-year cumulative risk of leukemic transformation was 31%. Circulating blasts ≥1% significantly predicted inferior LFS (P?=?0.04). The international prognostic scoring system (IPSS) and dynamic IPSS were not significant survival predictors in our cohort. Eighteen patients underwent allogeneic hematopoietic stem cell transplantation. The median OS post-transplantation was merely 19 months.

Discussion: Platelet count?<100?×?10⁹/l, unfavorable karyotypes, and circulating blasts >1% were negative prognostic indicators.

Conclusion: Chinese MF patients were similar to Western patients in clinicopathologic features and outcome.     

老年早期胃癌临床病理特点及预后因素分析

目的探讨老年早期胃癌的临床病理特征和预后因素，为老年早期胃癌的诊断和治疗提供理论依据。方法回顾性分析该院57例老年早期胃癌患者的临床病理资料及预后。结果老年早期胃癌最常见症状是上腹不适和隐痛。3年和5年生存率为100．0％和91．8％。胃镜病理活检确诊率为94．6％。胃上部黏膜下癌3例，淋巴结转移限于第1站；胃中部黏膜下癌10例，其中胃左动脉旁淋巴结转移4例；胃下部黏膜下癌20例，其中左动脉旁淋巴结转移3例、肝总动脉旁淋巴结转移4例、腹腔动脉旁淋巴结转移1例。癌浸润深度和组织学分型是老年人早期胃癌独立的预后因素（P=0．001）。结论早期诊断、早期治疗是提高生存率的关键。浸润深度和组织学分型是老年早期胃癌独立的预后因素。建议对老年早期胃癌组织学分型分化差且侵及黏膜下层者宜行D1＋根治术式。     

Prognostic value of serum heavy/light chain ratios in patients with POEMS syndrome

POEMS syndrome is a rare plasma cell dyscrasia. Serum concentrations of the monoclonal protein in this disorder are typically low, and inapplicable to monitor disease activity in most cases, resulting in limited practical and prognostic values. Novel immunoassays measuring isotype‐specific heavy/light chain (HLC) pairs showed its utility in disease monitoring and outcome prediction in several plasma cell dyscrasias. We report results of HLC measurements in 90 patients with POEMS syndrome. Sixty‐six patients (73%; 95% confidence interval, 63–82%) had an abnormal HLC ratio at baseline. It could stratify the risk of disease relapse and was strongly associated with worse progression‐free survival in a multivariate analysis (P = 0.021; hazard ratio [HR] 6.89, 95% CI 1.34–35.43). After therapy, HLC ratios improved, with 43 patients (48%) remaining abnormal. The post‐therapeutic HLC ratio, if abnormal, also remained as an independent prognostic factor associated with worse progression‐free survival (P = 0.019; HR 4.30, 95% CI 1.27–14.56). These results suggest the prognostic utility of HLC ratios in clinical management of POEMS patients.     

Usefulness of a free light chain immunoassay in serum for the diagnosis and the follow-up of monoclonal gammopathy

PURPOSE: Monoclonal immunoglobulin free light chains (FLC) are present in the serum and urine of many patients with monoclonal gammopathies. In this review, we discuss the usefulness of serum FLC determination for diagnostic, prognostic and monitoring of multiple myeloma (MM), AL amyloidosis and monoclonal gammopathies of undetermined significance (MGUS). CURRENT KNOWLEDGE AND KEY POINTS: Serum FLC assay is a useful laboratory test for management of light chain MM, non-secretory MM and AL amyloidosis. Currently, serum FLC testing cannot be recommended for monitoring intact immunoglobulin multiple myeloma. Even though serum FLC determination give a better risk stratification for MGUS, systematic serum FLC assay should not be used in routine because of high MGUS occurrence in the general population. FUTURE PROSPECTS AND PROJECTS: Further prospective studies with large cohorts of patients should provide additional evidence for the role of serum FLC measurement in patients with intact immunoglobulin multiple myeloma.     

Clinical features,laboratory characteristics and outcomes of patients with renal versus cardiac light chain amyloidosis

This study evaluated the differences in clinical features of 1077 newly diagnosed AL amyloidosis patients with renal involvement (n = 229, 21%), both cardiac and renal involvement (n = 443, 41%) and cardiac involvement (n = 405, 38%). Significant differences in dFLC (difference in involved and uninvolved light chains) were noted (renal, both, cardiac median: 83, 234 and 349 mg/l, P < 0.001). The proportion of patients with ≥ 10% bone marrow plasma cells (BMPCs) was lowest in renal only patients: 44%, 57%, 64%, respectively, P < 0.001. In a multivariate linear regression model incorporating organ involvement type and BMPCs ≥10%, organ involvement was a significant predictor of dFLC (P < 0.001). Median overall survival (OS) across the three groups was 83 vs. 19 vs. 16 months (P < 0.001) in patients not undergoing transplant and 5-year OS in patients undergoing transplant was 90% vs. 75% vs. 64% (P = 0.007), respectively. In conclusion, renal involvement alone or renal + cardiac involvement in AL amyloidosis is associated with lower circulating light chain burden, which cannot be fully explained by BMPC burden alone. Increased sensitivity of the kidney to light chains, given significant interactions with the renal tubular system and secretion of modified light chain products may play a role in pathogenesis of renal AL amyloidosis and warrants further investigation.     

Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare paraneoplastic syndrome in which nearly all patients have a monoclonal lambda restricted plasma cell disorder. We investigated whether patients with POEMS have abnormal serum immunoglobulin free light chain (FLC) ratios. Fifty patients with newly diagnosed POEMS syndrome were assessed. Cystatin C levels were measured to discern whether subclinical renal insufficiency could account for FLC elevations in the presence of a normal FLC ratio. Forty‐five patients (90%) had elevated lambda FLC; however, only nine (18%) had abnormal FLC ratios. The rise in serum FLC of POEMS patients appeared to be multifactorial—both a function of subclinical renal insufficiency and polyclonal activation of medullary and extramedullary plasma cells. Those patients expressing a clonal IgA were more likely to have clonal plasmacytosis observed on iliac crest biopsy than those with IgG. In summary, serum immunoglobulin profiles are unique in POEMS syndrome as compared with other plasma cell disorders. Am. J. Hematol. 2010. © 2010 Wiley‐Liss, Inc.     

Abnormal immunoglobulin synthesis in monoclonal immunoglobulin light chain and light and heavy chain deposition disease.

The Congo red-binding fibrils of AL amyloidosis are the most common form of monoclonal immunoglobulin tissue deposition (MIDD). Nonetheless, the less structured deposits found in light chain deposition disease (LCDD) and the similar, but distinct, deposits of light and heavy chain deposition disease (LHCDD) and heavy chain deposition disease (HCDD) can produce significant clinical pathology. Analyses of immunoglobulin synthesis by bone marrow cells obtained from 7 patients with LCDD and LHCDD demonstrated the production of excess light chains in all and the presence of incomplete light chains or heavy chain fragments in 5, regardless of the presence of an intact monoclonal protein or related subunit in the serum or urine. Our data indicate that, as is the case with the fibrillar deposits of AL amyloid, the non-fibrillar forms of monoclonal Ig deposition (LCDD and LHCDD) can be associated with the presence of immunoglobulin fragments in bone marrow cells. In some instances these appeared to be synthetic in origin, although rapid intracellular proteolysis or a combination of both could not be excluded. In either case the fragments may be more susceptible to tissue deposition, with subsequent organ compromise, than intact Ig chains.     

成人烟雾病16例临床和影像学特点研究

目的探讨成人烟雾病(MMD)的临床和影像学特征。方法回顾性总结2006年1—12月在山东大学齐鲁医院经脑血管造影证实的16例成人MMD患者的临床及影像学特征。结果 16例患者平均年龄为(40.8±9.8)岁;15例(93.75%)以缺血性脑血管病为首发症状;1例(6.25%)以非典型血管病为首发症状;无脑出血患者。颅内有梗死灶或出血性梗死灶者12例(85.7%);双侧颈内动脉(ICA)末端、大脑中动脉(MCA)和(或)大脑前动脉(ACA)起始部狭窄或闭塞、伴有脑底部异常血管网及侧支循环形成的13例(92.9%);仅表现为脑动脉硬化者1例(7.1%)。双侧ICA末端及ACA、MCA起始部不同程度狭窄或闭塞者10例(62.5%);单侧血管病变者6例(37.5%);可见不同程度的侧支循环形成者15例(93.8%);烟雾状血管形成者13例(81.2%)。结论成人MMD患者的临床表现以缺血性症状为主,发病年龄高峰在40岁左右。影像学特征为双侧ICA狭窄或闭塞,伴有MCA或ACA的狭窄或闭塞,颅底有不同程度异常增生的血管网。对于青壮年反复出现脑梗死者,应考虑MMD的可能并及早行MRA或DSA检查。