Monoclonal Immunoglobulin Light-chain Amyloidosis Research Articles

Value of nuclide scintigraphy in the diagnosis and prognosis of cardiac amyloidosis.

Amyloidosis is a local or systemic disease caused by the deposition of misfolded proteins outside the cell, with rapid progression, and dire prognosis. Common types of cardiac amyloidosis are monoclonal immunoglobulin light chain amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA). Nuclear medicine examinations can be accurate, rapid, and non-invasive to help diagnose diseases and can effectively predict the prognosis of patients with CA. Technetium (99Tcm)-labeled bisphosphonate imaging has been included in the consensus of experts and has become the first-line imaging method for the diagnosis of ATTR-CA. 123I-metaiodoenzylguanidine (MIBG) as a norepinephrine analogue can effectively assess cardiac sympathetic innervation in patients with CA. Aβ- amyloid imaging agents such as 11C-pittsburgh compound B and 18F-flubetaben are expected to be new techniques for diagnosing AL-CA and incorporating them into cardiac staging systems for AL-CA patients in the future. New imaging agents such as 18F-NaF has been widely used in the diagnosis, treatment response monitoring, and prognosis assessment of CA. Summarizing the research value of nuclide imaging in CA may provide new ideas for clinical realization of early detection of CA and accurate assessment of disease prognosis.

Cardiac Amyloidosis Imaging, Part 3: Interpretation, Diagnosis, and Treatment.

Cardiac amyloidosis was thought to be rare, undiagnosable, and incurable. However, recently it has been discovered to be common, diagnosable, and treatable. This knowledge has led to a resurgence in nuclear imaging with 99mTc-pyrophosphate-a scan once believed to be extinct-to identify cardiac amyloidosis, particularly in patients with heart failure but preserved ejection fraction. The renewed interest in 99mTc-pyrophosphate imaging has compelled technologists and physicians to reacquaint themselves with the procedure. Although 99mTc-pyrophosphate imaging is relatively simple, interpretation and diagnostic accuracy require an in-depth knowledge of amyloidosis etiology, clinical manifestations, disease progression, and treatment. Diagnosing cardiac amyloidosis is complicated because typical signs and symptoms are nonspecific and usually attributed to other cardiac disorders. In addition, physicians must be able to differentiate between monoclonal immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Several clinical and noninvasive diagnostic imaging (echocardiography and cardiac MRI) red flags have been identified that suggest a patient may have cardiac amyloidosis. The intent of these red flags is to raise physician suspicion of cardiac amyloidosis and guide a series of steps (a diagnostic algorithm) for narrowing down and diagnosing the specific amyloid type. One element in the diagnostic algorithm is to identify monoclonal proteins indicative of AL. Monoclonal proteins are detected by serum or urine immunofixation electrophoresis and serum free light-chain assay. Another element is identifying and grading cardiac amyloid deposition using 99mTc-pyrophosphate imaging. When monoclonal proteins are present and the 99mTc-pyrophosphate scan is positive, the patient should be further evaluated for cardiac AL. The absence of monoclonal proteins and a positive 99mTc-pyrophosphate scan is diagnostic for cardiac ATTR. Patients with cardiac ATTR need to undergo genetic testing to differentiate between wild-type ATTR and variant ATTR. This article is the third in a 3-part series in this issue of the Journal of Nuclear Medicine Technology Part 1 reviewed amyloidosis etiology and outlined 99mTc-pyrophosphate study acquisition. Part 2 described 99mTc-pyrophosphate image quantification and protocol technical considerations. This article discusses scan interpretation along with cardiac amyloidosis diagnosis and treatment.

Increasing the accuracy of proteomic typing by decellularisation of amyloid tissue biopsies

Diagnosis and treatment of systemic amyloidosis depend on accurate identification of the specific amyloid fibril protein forming the tissue deposits. Confirmation of monoclonal immunoglobulin light chain amyloidosis (AL), requiring cytotoxic chemotherapy, and avoidance of such treatment in non-AL amyloidosis, are particularly important. Proteomic analysis characterises amyloid proteins directly. It complements immunohistochemical staining of amyloid to identify fibril proteins and gene sequencing to identify mutations in the fibril precursors. However, proteomics sometimes detects more than one potentially amyloidogenic protein, especially immunoglobulins and transthyretin which are abundant plasma proteins. Ambiguous results are most challenging in the elderly as both AL and transthyretin (ATTR) amyloidosis are usually present in this group. We have lately described a procedure for tissue decellularisation which retains the structure, integrity and composition of amyloid but removes proteins that are not integrated within the deposits. Here we show that use of this procedure before proteomic analysis eliminates ambiguity and improves diagnostic accuracy. SignificanceUnequivocal identification of the protein causing amyloidosis disease is crucial for correct diagnosis and treatment. As a proof of principle, we selected a number of cardiac and fat tissue biopsies from patients with various types of amyloidosis and show that a classical procedure of decellularisation enhances the specificity of the identification of the culprit protein reducing ambiguity and the risk of misdiagnosis.

Low Levels of Serum N-3 Polyunsaturated Fatty Acids are Associated with Lower Heart Failure Free Survival after Acute Myocardial Infarction

Introduction: Cardiac involvement in systemic amyloidosis causes detrimental prognosis, therefore early detection and classification are important to develop appropriate therapeutic strategies. Subcutaneous tissue biopsy is a useful screening for systemic amyloidosis; however, its diagnostic and prognostic value in patients with cardiac amyloidosis remains elusive. Methods: We retrospectively analyzed 14 consecutive patients with cardiac amyloidosis who underwent subcutaneous tissue biopsy. Results: Amyloid deposition was observed in 11 patients (79%). Histopathological analysis demonstrated that acquired monoclonal immunoglobulin light-chain amyloidosis could be predicted when the degree of amyloid deposition was greater in blood vessels than adipose tissue compare to senile systemic amyloidosis and familial amyloidosis (60% vs. 0%; p50.03). During the follow-up period (median 297 days, range 3-761 days), 7 patients died or were admitted to the hospital due to worsening heart failure. Among them, 6 patients (86%) were positive for amyloid deposition in blood vessels. The incidence of death and composite outcome, including heart failure hospitalization and death, was significantly higher in patients positive for amyloid deposition in blood vessels than in those without (p50.03, p50.006; respectively). Conclusions: Amyloid subtype could be diagnosed by analyzing the degree of amyloid deposition in blood vessels and adipose tissue using subcutaneous tissue biopsy samples in patients with cardiac amyloidosis. Amyloid deposition in blood vessels suggests poor prognosis of these patients.

Effect of Exercise Training on Nitric Oxide Synthasesin the Cardiovasculature and Kidney of Rats with Chronic Heart Failure

Introduction: Cardiac involvement in systemic amyloidosis causes detrimental prognosis, therefore early detection and classification are important to develop appropriate therapeutic strategies. Subcutaneous tissue biopsy is a useful screening for systemic amyloidosis; however, its diagnostic and prognostic value in patients with cardiac amyloidosis remains elusive. Methods: We retrospectively analyzed 14 consecutive patients with cardiac amyloidosis who underwent subcutaneous tissue biopsy. Results: Amyloid deposition was observed in 11 patients (79%). Histopathological analysis demonstrated that acquired monoclonal immunoglobulin light-chain amyloidosis could be predicted when the degree of amyloid deposition was greater in blood vessels than adipose tissue compare to senile systemic amyloidosis and familial amyloidosis (60% vs. 0%; p50.03). During the follow-up period (median 297 days, range 3-761 days), 7 patients died or were admitted to the hospital due to worsening heart failure. Among them, 6 patients (86%) were positive for amyloid deposition in blood vessels. The incidence of death and composite outcome, including heart failure hospitalization and death, was significantly higher in patients positive for amyloid deposition in blood vessels than in those without (p50.03, p50.006; respectively). Conclusions: Amyloid subtype could be diagnosed by analyzing the degree of amyloid deposition in blood vessels and adipose tissue using subcutaneous tissue biopsy samples in patients with cardiac amyloidosis. Amyloid deposition in blood vessels suggests poor prognosis of these patients.

Diagnostic and Prognostic Value of Subcutaneous Tissue Biopsy in Patients With Cardiac Amyloidosis

Cardiac involvement in systemic amyloidosis causes detrimental prognosis; therefore, early detection and classification are important to develop appropriate therapeutic strategies. Subcutaneous tissue biopsy is a useful screening procedure for systemic amyloidosis; however, its diagnostic and prognostic value in patients with cardiac amyloidosis remains elusive. Thus, we investigated the value of subcutaneous tissue biopsy in cardiac amyloidosis. In 22 patients with cardiac amyloidosis, we retrospectively analyzed 14 consecutive patients with cardiac amyloidosis who underwent subcutaneous tissue biopsy. Amyloid deposition was observed in 11 patients (79%). Histopathologic analysis demonstrated that acquired monoclonal immunoglobulin light-chain amyloidosis could be predicted when the degree of amyloid deposition was greater in blood vessels than adipose tissue compared to senile systemic amyloidosis and familial amyloidosis (60% vs 0%, p = 0.03). During the follow-up period (median 297 days, range 3 to 761), 7 patients (5 with monoclonal immunoglobulin light-chain amyloidosis and 2 with senile systemic amyloidosis) died or were admitted to the hospital because of worsening heart failure. Of them, 6 patients (86%) were positive for amyloid deposition in blood vessels in subcutaneous tissue biopsy. Incidence of death and composite outcome including heart failure hospitalization and death was significantly higher in patients positive for amyloid deposition in blood vessels than in those without (p = 0.03, p = 0.006, respectively). These results suggest that amyloid subtype could be diagnosed by assessing the degree of amyloid deposition in blood vessels and adipose tissue in subcutaneous tissue biopsy samples from patients with cardiac amyloidosis. Amyloid deposition in blood vessels suggests poor prognosis of these patients.

Renal amyloidosis caused by apolipoprotein A-II without a genetic mutation in the coding sequence

Although the majority of renal amyloidosis is caused by either acquired monoclonal immunoglobulin light-chain amyloidosis or reactive systemic amyloid A, some cases are caused by hereditary amyloidosis. Apolipoprotein A-II (apoAII) amyloidosis is a rare form of hereditary amyloidosis and cannot be diagnosed by a routine examination. Thus, the prevalence and etiology of apoAII amyloidosis are uncertain. In humans, a genetic mutation in the stop codon of apoAII is considered to be a cause of amyloid fibril formation. We report on a 68-year-old man who presented with proteinuria by apoAII amyloidosis without family history. His proteinuria gradually increased to 6g/day within 1year. A renal biopsy showed amyloid deposition in the glomeruli, however, acquired monoclonal immunoglobulin light-chain amyloidosis and reactive systemic amyloid A were ruled out. Immunohistochemistry revealed apoAII deposition in the glomeruli, but DNA sequencing did not identify any genetic mutation in the coding sequence of apoAII. Here, we report a case of apoAII amyloidosis without a genetic mutation in the coding sequence and discuss the etiology of apoAII amyloidosis.

Mass Spectrometric–Based Proteomic Analysis of Amyloid Neuropathy Type in Nerve Tissue

To determine the specific type of amyloid from nerve biopsies using laser microdissection (LMD) and mass spectrometric (MS)-based proteomic analysis. Twenty-one nerve biopsy specimens (17 sural, 3 sciatic, and 1 root amyloidoma) infiltrated by amyloid were studied. Immunohistochemical subtyping was unable to determine the specific amyloid type for these 21 cases, but the clinical diagnosis was made based on additional testing. Clinical diagnosis was made through evaluation of serum monoclonal proteins, biopsy of bone marrow for acquired monoclonal immunoglobulin light chain amyloidosis, and kindred evaluations with DNA sequencing of transthyretin (TTR) and gelsolin (GSN) genes. Our study included 8 cases of acquired monoclonal immunoglobulin light chain amyloidosis, 11 cases of transthyretin amyloidosis (3 with the Val30Met mutation, 2 with the Val32Ala mutation, 2 with the Thr60Ala mutation, 1 with the Ala109Ser mutation, 1 with the Phe64Leu mutation, 1 with the Ala97Ser mutation, and 1 not sequenced), and 2 cases of gelsolin amyloidosis (1 with the Asp187Asn mutation and 1 not sequenced). One patient with transthyretin amyloidosis and 1 patient with gelsolin amyloidosis with no specific mutation identified were diagnosed based on genetic confirmation in their first-degree relative. Congophilic proteins in the tissues of these 21 cases underwent LMD, were digested into tryptic peptides, and were analyzed using liquid chromatography electrospray tandem MS. Identified proteins were reviewed using bioinformatics tools with interpreters blinded to clinical information. Specific amyloid type was ascertained by LMD tandem MS and compared with clinical diagnosis. Specific types of amyloid were accurately detected by LMD/MS in all cases (8 cases of acquired monoclonal immunoglobulin light chain amyloidosis, 2 cases of gelsolin amyloidosis, and 11 cases of transthyretin amyloidosis). Incidental serum monoclonal proteins did not interfere with detection of transthyretin amyloidosis in 2 patients. Additionally, specific TTR mutations were identified in 10 cases by LMD/MS. Serum amyloid P-component and apolipoprotein E proteins were commonly found among all cases. Proteomic analysis of nerve tissue using LMD/MS distinguishes specific types of amyloid independent of clinical information. This new proteomic approach will enhance both diagnostic and research efforts in amyloidosis and other neurologic diseases.

Lysozyme Amyloidosis

Autosomal dominant hereditary amyloidosis represents not 1 disease but a group of diseases, each the result of mutations in a specific protein. The most common form is transthyretin amyloidosis, which has been recognized clinically for over 50 years as a familial polyneuropathy. Nonneuropathic amyloidoses (Ostertag type amyloidosis) include those due to abnormalities in lysozyme, fibrinogen Aalpha-chain, and apolipoprotein A-I and A-II. The role of lysozyme in amyloid-related human disorders was first described in 1993; to date, there have been only 9 publications describing this disorder, which is a nonneuropathic form of hereditary amyloidosis. Reported cases have involved 7 unrelated families. We describe here our own experience with 4 families suffering from lysozyme amyloidosis: the first had prominent renal manifestations with sicca syndrome, the second and third had prominent gastrointestinal symptoms, and the fourth had a dramatic bleeding event due to rupture of abdominal lymph nodes. To our knowledge, this last symptom has not been reported previously, but is reminiscent of the hepatic hemorrhage seen in a previously reported case of a patient with lysozyme amyloidosis. To characterize the manifestations of this disorder, we performed an exhaustive literature review.Although hereditary amyloidosis is thought to be a rare disease, it is probably not as rare as we think and may well be underdiagnosed. Moreover, some cases of lysozyme amyloidosis are probably confused with acquired monoclonal immunoglobulin light-chain (AL) amyloidosis, formerly known as primary amyloidosis, which is the most frequent type of amyloidosis. Because treatment for each type of amyloidosis is different, and because therapy directed at 1 type may worsen symptoms of the other types, it is important to determine precisely the nature of the amyloid protein. Thus, hereditary lysozyme amyloidosis should be considered in all patients with systemic amyloidosis, particularly in patients who present with renal, gastrointestinal, or bleeding complications without evidence of AL or AA (secondary) amyloidoses.

Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis.

Systemic monoclonal immunoglobulin light chain amyloidosis (AL) is associated with clonal plasma cell dyscrasias that are often subtle and non-proliferating. AL shares numerical chromosomal changes with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). Illegitimate translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and deletions of the long arm of chromosome 13, [del(13q)], commonly occur in MM, MGUS and plasma cell leukaemia. In AL IGH rearrangements have been identified but, to date, there are no reports of del(13q). In this study of 32 patients with AL, 24 with systemic and eight with localized disease, translocations involving IGH and del(13q) were found using dual-colour interphase fluorescence in situ hybridization (FISH). IGH translocations were observed in 11 patients (37% overall and in 46% with systemic disease), of which nine had the IGH/CCND1 fusion from t(11;14)(q13;q32). Two showed IGH translocations other than the t(11;14) or t(4;14)(p16;q32). In one of these patients a breakpoint within the constant region of IGH between Calpha1 and Calpha2 was indicated. In the second a deletion covering Calpha1 and Calpha2 accompanied the translocation. Ten patients (27% overall and 33% of those with systemic disease) showed del(13q). The gain or loss of IGH and CCND1 signals provided evidence of numerical chromosomal changes in three patients.