Urinary Findings in Renal Light Chain–Derived Amyloidosis and Light Chain Deposition Disease

BackgroundEarly recognition of light chain—derived (AL) amyloidosis and light chain deposition disease (LCDD) is essential for optimal therapy. However, clinical and laboratory manifestations of these unusual conditions often go unrecognized. Renal protein deposits in AL amyloidosis and LCDD can cause both heavy albuminuria and Bence Jones proteinuria. Absent separate etiologies, this combined finding is rare and provides a clue to the diagnosis of these conditions.Materials and MethodsWe retrospectively reviewed test results of urine immunoelectrophoreses and urine immunofixation electrophoreses performed at a single institution from 1977 to 2006. Patients with both heavy albuminuria and Bence Jones proteinuria were investigated further to determine whether these findings were predictive of renal AL amyloidosis or LCDD. We reviewed the patients' clinical histories, laboratory data, and pathology reports and included patients with biopsy-confirmed renal AL amyloidosis or LCDD in this series.ResultsWe identified 6 patients with renal amyloidosis or LCDD who presented with the dual findings of Bence Jones proteinuria and heavy albuminuria. We report their demographic information, laboratory data, and case histories.ConclusionThe simultaneous presence of heavy albuminuria and Bence Jones proteinuria justifies a workup for AL amyloidosis or LCDD. Prompt recognition of these rare conditions would permit earlier initiation of therapy and potentially limit organ dysfunction. In addition, patients might be spared unnecessary clinical investigation and unwarranted treatment.     

Lymphadenopathy due to amyloid deposition in non-Hodgkin's lymphoma

Background: Amyloidosis is a rare complication of non-Hodgkin'slymphoma. Most of the reported patients have had systemic amyloidosis and havedied as a result of complications of this disease.Materials and methods: The clinical cases of two patients withlymphoplasmacytic non-Hodgkin's lymphoma who presented with lymphadenopathydue to localised amyloid deposition are reviewed. Immunohistochemical studieswere performed on the amyloid deposits and adjacent lymphoma.Results: The amyloid deposits in both patients were derived frommonoclonal light chains of the same isotype as those expressed by the lymphomacells and were localised to areas adjacent to the lymphoma despite thepresence of circulating light chains. Both patients had an indolent clinicalcourse and treatment appeared to have little influence on the amyloiddeposition.Conclusions: Non-Hodgkin's lymphoma may be associated with localisedamyloidosis secondary to local production and deposition of amyloid frommonoclonal light chains synthesised by the lymphoma cells. This is a rarecause of lymphadenopathy which does not respond to treatment of the underlyinglymphoma.     

Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease.

All forms of MIDD are related to the presence of an expanded clone of B-cell origin that is producing an Ig product, usually, but not exclusively an L-chain, which is predisposed to deposit in tissues, with or without some degree of processing. The nature of the processing is currently unclear, although limited proteolysis is likely to play a major role in most, but not all, patients. Diagnosis is made by the identification, using immunohistochemical techniques, of the monoclonal Ig nature of the deposited material, which may be fibrillar and Congo red-positive (AL and AH), or more amorphous and Congo red-negative (LCDD and LCHDD). Present modalities of therapy are similar or identical to those employed in multiple myeloma, attempting to eliminate the monoclonal cell population responsible for the production of the precursor of the deposited protein. A variety of ancillary therapeutic measures may be employed to treat problems associated with the failure of specific organs produced by the deposition. The details of how the uniformly soluble precursor molecule is converted to an essentially insoluble aggregate that compromises the function of the tissue in which it is formed are not yet known. It is still not possible to construct a potential "unified field theory" governing the deposition of intact Igs or their fragments. It is likely, as appears to be the case in other forms of amyloid unrelated to Ig, that many proteins contain, within their sequence, peptides that are capable of forming insoluble beta sheet-like structures. When these peptides are isolated from their surrounding molecular environment--either by proteolysis in the test tube, by a mutational change that predisposes them to limited proteolysis; or by a point mutation, deletion, or some other structural modification (as glycosylation), which alters their molecular context without proteolysis--and are present in sufficient concentration, they become less soluble under physiologic conditions. It is likely that the site of deposition depends upon the site of synthesis, but to a lesser extent than the protease profile and the physicochemical make-up of the affected tissues. Better understanding of the latter factors is necessary for the development of better modes of treatment.     

Bortezomib-based chemotherapy for light chain deposition disease presenting as acute renal failure

We report a case of kappa light chain deposition disease (LCDD) associated with multiple myeloma in a patient presenting with acute renal failure, 2+ proteinuria and hypercalcemia. Serum protein electrophoresis showed an M-spike at 0.1 g/dL. 24-h urine protein electrophoresis showed Bence-Jones proteinuria of 3.8 g. Serum-free light chain assay found excess kappa chains at 3080 mg/L, with normal lambda and an elevated kappa:lambda ratio of 124.7. A kidney biopsy revealed kappa light chain nephropathy with PAS-negative tubular casts in the cortex and outer medulla. Bone marrow biopsy showed 15% kappa-restricted plasma cells. Serum beta-2 microglobulin level was elevated at 7.94 mg/dL. The patient received a 3-day course of plasmapheresis followed by eight cycles of bortezomib (Velcade®), liposomal doxorubicin, and dexamethasone (VDD) and did not require hemodialysis. As partial response was not achieved, treatment was continued with three cycles of bortezomib, cyclophosphamide, dexamethasone, and thalidomide, followed by thalidomide maintenance at 100 mg daily. Thirty-two months after the diagnosis, the patient’s renal function was improved and he achieved a partial response. This case underlines the feasibility and effectiveness of bortezomib-based chemotherapy in the treatment of LCDD with severe renal dysfunction.     

Laser in treatment of laryngeal amyloidosis

Amayloidosis is the extracellular deposition of the fibrinous protein amyloid in one or more body sites. Amyloidosis may broadly be classifed as either primary or secondary. Primary amyloidosis is idiopathic (56 %), whereas the secondary form is associated with a chronic inflammatory or infectious process (5%). Amyloidosis is also related to multiple myeloma (26%), senescence (5%) and where tumor like deposits occur in isolated organ without systemic involvement (8%). Laryngeal amyloidosis is a rare disease. Surgery has been the mainstay of treatment either endoscopicalfy or by an external neck approach. One case of laryngeal amyloidosis, treated with endolaryngeal microsurgery and carbon dioxide laser is presented with a follow up of 8 years.     

Head and neck amyloidosis: a clinicopathologic study of 15 cases

Amyloidosis refers to the idiopathic, extracellular deposition of fibrillar proteins, termed amyloid, in tissues. Although amyloidosis is a rare disease, the head and neck region has been reported as a frequent site of amyloid deposits, accounting for approximately 19% of reported amyloid cases in one review. Fifteen cases of head and neck amyloid, excluding the brain, with clinical follow-up were identified in the Surgical Pathology files from 1985 to 2005 at Emory University Hospital. The histopathology, histochemistry, and patient follow-up were reviewed. Nine men and six women with an age range of 18-76 years (mean 55.7 years) were identified. The initial clinical presentation was dependent on the site of amyloid deposits. The clinical types of amyloidosis included localized amyloid deposits in the larynx and tongue, plasma cell dyscrasia associated AL amyloidosis, and hemodialysis-associated amyloidosis. Secondary amyloidosis developed in one patient with carcinoid tumor.     

Laser in treatment of laryngeal amyloidosis: A case report

Amyloidosis is the extracellular deposition of the fibrinous protein amyloid in one or more body sites. Amyloidosis may broadly be classified as either primary or secondary. Primary amyloidosis is idiopathic (56%), whereas the secondary form is associated with a chronic inflammatory or infectious process (5%), Amyloidosis is also related to multiple myeloma (26%). senescence (5%) and where tumor like deposits occur in isolated organs without systemic involvement (8%). Laryngeal amyloidosis is a rare discase. Surgery has been the mainstay of treatment either endoscopically or by an external neck approach. One case of laryngeal amyloidosis, treated with endolaryngeal microsurgery and carbon dioxide laser is presented with a follow up of 8 years.     

多发性骨髓瘤肾脏病变的研究进展

 多发性骨髓瘤（MM）患者肾损害谱包括"骨髓瘤肾"或管型肾病、轻链淀粉样变、单克隆免疫球蛋白沉积病、冷球蛋白血性肾小球肾炎和增生性肾小球肾炎等。MM肾脏病患者肾活组织病理检查研究显示,管型肾病占40 %～63 %,肾轻链沉积病（LCDD）占19 %～26 %,淀粉样变占7 %～30 %,冷球蛋白肾病＜1 %。管型肾病、MIDD和淀粉样变的肾病理学不同。骨髓瘤相关肾病的肾外表现较多样,进展为肾功能不全和末期肾病（ESRD）发生率高,并发症增加,死亡率显著升高,合并肾病的MM患者生存期和肾生存期短。治疗包括MM化疗、血液透析和自体造血干细胞移植（ASCT）等,ASCT有血液学反应和肾反应者的生存率明显改善,成功的ASCT给更多的患者以肾和其他脏器移植的机会。     

Amyloidosis

Opinion statement Amyloidosis is a disease in which abnormal proteins form fibrillar tissue deposits that can compromise key viscera and lead to early death. In order to treat amyloidosis, the type of abnormal protein must be identified. The most common type is monoclonal immunoglobulin light chain or AL amyloidosis; the other important type is hereditary, caused by variant forms of transthyretin and other proteins, whereas amyloid associ-ated with chronic inflammation (“secondary≓) is rare in the developed world. AL can be misdiagnosed if a monoclonal gammopathy and a hereditary variant are present in the same patient. The aim of therapy in systemic AL amyloidosis is to reduce the amyloid-forming monoclonal light chain, measured with the serum free light chain assay, by suppressing the underlying plasma cell dyscrasia, while using supportive measures to sustain organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor light chain is eliminated. The most effective treatment for systemic AL amyloidosis is risk-adapted melphalan with peripheral blood stem cell transplant (SCT). The hematologic response rate is 75% at 12 months when adjuvant therapy with thalidomide and dexamethasone is used post-SCT. Patients can achieve long-term durable remissions with organ recovery. Drugs effective in multiple myeloma are usually helpful in AL amyloidosis if tolerated. The use of novel antibody-based approaches for imaging amyloid and possibly for accelerating removal of deposits is under active investigation.     

Secondary amyloidosis and eosinophilia in a patient with uterine leiomyosarcoma

We report a rare case demonstrating the relationship between secondary amyloidosis and uterine leiomyosarcoma. A 59-year-old female with high fever was referred to our hospital. Laboratory tests revealed increased white blood cells, eosinophilia and an accelerated erythrocyte sedimentation rate. Endoscopic examination of the stomach and colon revealed amyloid deposits in their mucosa. The patient showed no symptoms that suggested amyloidosis. No other organs or tissues were surveyed for amyloid deposition. Ga scintigraphy, computed tomography and magnetic resonance imaging suggested necrotic infectious leiomyoma of the uterus, which was considered to be the cause of the fever. The patient underwent total hysterectomy. The histological diagnosis of the mass revealed a low-grade uterine leiomyosarcoma with necrosis. Amyloid deposits in the gastric mucosa disappeared 1 year after the operation. In this case, amyloid deposition was detected by endoscopic biopsy before clinical manifestations. The deposition was reversible and was successfully treated. Thus, it is logical and useful to undertake endoscopic mucosa biopsy to check for amyloid deposition in patients with systemic inflammation, whose serum amyloid A protein level has been high for several months. In addition, peripheral eosinophilia was also detected in this case. Although eosinophilia associated with malignant tumor has been recognized, it is an uncommon occurrence.     

Primary (AL) amyloidosis in plasma cell disorders

Primary (AL) amyloidosis is the most common form of systemic amyloidosis. The morbidity arises from extracellular deposition of immunoglobulin light chain (LC) fibrils in major organs, such as the kidneys, heart, and bowel. Organ dysfunction contributes to a high mortality and poor prognosis, with a median survival time of 1-2 years from diagnosis. Here, we present a 46-year-old man with an exceptional clinical course of an LC multiple myeloma with generalized amyloidosis, causing renal insufficiency, congestive heart failure, and complete intestinal necrosis. We have summarized recent knowledge on AL amyloidosis, its association with monoclonal gammopathies, clinical presentations, diagnostic tools, and treatment strategies. Our comprehensive overview of this rare and often fatal disease aims to increase the awareness of AL amyloidosis. This may facilitate earlier diagnosis, and thus allow initiation of prompt and specific therapies, which are indispensable in order to improve disease prognosis.     

Papillary carcinoma in amyloid goitre

Amyloid goitre is a rare lesion characterized by a diffuse and bilateral enlargement of the thyroid gland due to amyloid deposition. It is uncommon that a massive and widespread amount of adipose tissue deposition is found within these lesions and only in exceptional cases a differentiated carcinoma can develop. We describe the third example of thyroid carcinoma, arising in a 74-year old female who had also massive adipose thyroidal metaplasia, within amyloid goitre. The Congo red stain confirmed the diagnosis of amyloid goitre. Immunohistochemistry showed reactivity with MoAb against amyloid fibril protein A. The patient suffered from renal failure of undetermined aetiology for three years, but neither systemic amyloidosis nor risk factors for its development were found. It is important to correctly diagnose amyloid goitre both to rule out the presence of a differentiated thyroidal carcinoma and to search for amyloid infiltration in other organs in view of an early appropriate therapy.     

Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis

Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.     

Extraosseus Plasmacytoma of the Pharynx with Localized Light Chain Deposition. Case Report

Light chain deposition disease (LCDD) is a rare disorder associated with a clonal proliferation of plasma cells, which synthesize abnormal monoclonal immunoglobulin light chains. It is characterized by systemic deposition of light chains in various organs, with the kidneys being most commonly affected. There have been few reports of isolated LCDD, i.e. in the brain, lungs and cervical lymph nodes. We here report on another patient with an isolated form of LCDD, which was limited to the pharyngeal mucosa and was associated with an extraosseus plasmacytoma of the pharynx, expanding the spectrum that has been recognized for LCDD. The patient was treated by local radiotherapy, with an excellent response. A less aggressive clinical course can probably be expected than in the usual form of LCDD, but a long-term follow-up is necessary to establish the clinical significance of this variant of LCDD.     

A case of a primary localized amyloidosis (amyloid tumor) of the renal pelvis and ureter

A 62-year-old woman complaining of asymptomatic hematuria was hospitalized. Although a cytologic examination of the urine was negative, abnormal findings in the right renal pelvis by DIP, RP and CT led us to suspect a pelvic tumor, and a right nephroureterotomy was performed. Light microscopy revealed deposits of amorphous, eosinophilic material in the pelvis and proximal portion of upper ureter, however tumor cells were not found. Electron microscopy revealed that these materials were aggregates of linear, non-branching fibrils, measuring about 8 nm in diameter. Histochemically, these were seen to be consistent with amyloid, producing an apple-orange birefringence with Congo red staining under a polarized light. Alkali Congo red staining after pretreatment of KMnO4 demonstrate that this amyloid protein was composed largely of AA protein in addition to lesser amounts of non-AA protein, and a primary localized amyloidosis (amyloid tumor) was diagnosed. A clinicopathologic study that was performed on 12 cases of primary localized amyloidosis of the pelvis, including our case, also is reported.     

分析多发性骨髓瘤伴发淀粉样变患者实验室检查指标的变化特征

  目的  报道多发性骨髓瘤（multiple myeloma，MM）伴发骨髓淀粉样变实验室指标特征，进一步分析MM伴发淀粉样变患者实验室检查指标的变化。  方法  临床诊断MM患者44例，骨髓涂片刚果红染色结合偏振光确定淀粉样变，将MM划分为淀粉样变阳性和阴性两组。分别对两组进行全血细胞、血清酶及免疫球蛋白含量测定。同时依据细胞形态学分析两组骨髓各系幼稚与成熟细胞及骨髓瘤细胞数量。  结果  MM发现骨髓淀粉样变阳性患者免疫标志物IgG含量明显低于阴性组，κ和λ含量均值有降低趋势，但是未见统计学差异。淀粉样变阳性患者血清LDH和LDH1活性明显高于阴性组，而PT、Alb、PA、Glo、血液RBC、WBC和PLT数量等指标无统计学差异。  结论  MM患者免疫球蛋白IgG含量降低及LHD和LDH1增高有可能作为辅助检查MM骨髓淀粉样变的标志物。      

Cardiac Amyloidosis: Diagnosis and Treatment Strategies

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.     

Retroperitoneal paraganglioma and systemic amyloidosis: a case report.

The case of a 50-year-old woman with a retroperitoneal paraganglioma and nephrotic syndrome is presented. After the tumor was removed deposits of amyloid material were observed in the paraganglioma, kidneys, and liver. There was no thrombosis of the renal vein. The clinical picture (fever and nephrotic syndrome) was similar to that of patients with amyloidosis associated with neoplasms. The nephrotic syndrome disappeared 8 months after the operation. The patient has not had fever or nephrotic manifestations over the past 4 years and is asymptomatic at the present time. We believe this to be the first reported case of paraganglioma associated with amyloidosis. Nor have we found any references to clinical and biological remission of the nephrotic syndrome following surgical removal of the concomitant neoplasm.     

Epidemiology and outcomes research for MGUS, myeloma and amyloidosis

The epidemiology of plasma cell dyscrasias clearly links to a complicated multi-factorial pathogenic pathway that at the individual patient level gives no clear indication of why the malignant process has occurred but factors in the environment and within the genome give clues and are discussed. MGUS is a pre-malignant disorder characterised by monoclonal plasma cell proliferation in the bone marrow and no end-organ damage; the patients are asymptomatic. Primary amyloidosis is a rare disorder that is characterised by deposition of amyloid fibrils composed of immunoglobulin light chain fragments; symptoms relate to the affected organ. Multiple myeloma is a malignant disease of plasma cells and with improvements in treatment, patients can now expect a doubling of median survival to 5 years, a 20% chance of surviving >10 years and a 50% chance of complete remission (CR), morphological and biochemical. The challenge is now to determine exactly what this means to the individual myeloma patient in terms of benefit, and to society as a whole and this is the basis of 'outcomes research' which is discussed in this review.