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Background: Technetium-99m-pyrophosphate ( 99m Tc-PYP) uptake in the internal oblique muscle (IOM), which is often observed in patients with wild-type transthyretin cardiac amyloidosis (ATTR-CA), indicates amyloid transthyretin (ATTR) deposition., Objective: This study aimed to assess the safety and efficacy of 99m Tc-PYP imaging-based computed tomography (CT)-guided core-needle biopsy of the IOM as a new extracardiac screening biopsy for confirming the presence of ATTR deposits., Methods: Patients with suspected ATTR-CA in whom myocardial tracer uptake was detected on chest- and abdomen-centered images of 99m Tc-PYP scintigraphy underwent CT-guided core-needle biopsy at the site with the highest tracer uptake in the IOM between September 2021 and November 2022., Results: All 18 consecutive patients (mean age, 86.3 years ± 6.5; 61.1% male) enrolled in the study showed 99m Tc-PYP uptake into the IOM. Adequate tissue samples were obtained from all patients except one without serious complications. Immunohistochemical analysis confirmed ATTR deposits in 16/18 (88.9%) patients. In the remaining two patients, ATTR deposits were observed via endomyocardial biopsy. All patients were diagnosed with wild-type ATTR-CA based on transthyretin gene sequence testing results., Conclusion: In wild-type ATTR-CA, 99m Tc-PYP imaging-based CT-guided core-needle biopsy of the IOM could be used as an extracardiac screening biopsy to confirm the presence of ATTR deposits.

Purpose: 99mTc-pyrophosphate (99mTc-PYP) uptake in the skeletal muscles is minimal in patients with transthyretin cardiac amyloidosis (ATTR-CA) when assessed qualitatively and quantitatively. We previously demonstrated moderate- to high-grade 99mTc-PYP uptake in the subcutaneous abdominal fat of some patients with ATTR-CA and showed that this abnormal finding could reflect the regional amyloid burden of this tissue. We aimed to investigate the frequency of 99mTc-PYP uptake in skeletal trunk muscles of patients with ATTR-CA., Methods: Chest- and abdomen-centered 99mTc-PYP scintigraphy images were obtained 2 hours after IV injections of the tracer (20 mCi) in 36 patients with ATTR-CA. The frequency of 99mTc-PYP uptake in the following 11 skeletal trunk muscles was investigated: pectoralis major, deltoid, subscapularis, infraspinatus, trapezius, latissimus dorsi, erector spinae, psoas major, abdominal oblique, rectus abdominis, and the gluteus muscles., Results: Ten of the 11 muscles were involved in patients with the highest number of 99mTc-PYP uptake in the skeletal trunk muscles examined, whereas no muscle was involved in a patient with the least uptake. The muscle with the highest rate of 99mTc-PYP uptake, observed in 34 of 36 patients (94.4%), was the abdominal oblique. No tracer uptake was observed in the psoas major. The frequency of radiotracer uptake in the remaining examined muscles was between those of abdominal oblique and psoas major muscles., Conclusions: Radiotracer uptake was often detectable in some skeletal trunk muscles of ATTR-CA, although the muscles of patients examined and the skeletal trunk muscles of 1 patient showed heterogeneity in the uptake of 99mTc-PYP., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Radionuclide imaging using bone-avid tracers plays a critical role in diagnosing transthyretin cardiac amyloidosis (ATTR-CA), but technetium-99m-pyrophosphate (PYP) rarely allows the detection of extracardiac amyloid infiltration. We retrospectively investigated the frequency of PYP uptake in the subcutaneous abdominal fat of patients with ATTR-CA and its relevance to the results of fine-needle aspiration biopsy (FNAB) of this tissue., Methods: Chest-centered images of PYP scintigraphy were obtained 2 h after the intravenous injection of the tracer (20 mCi), and the frequency of PYP uptake in the subcutaneous abdominal fat was evaluated. Amyloid deposits of fat smears taken by subcutaneous abdominal fat FNAB were assessed by Congo red staining., Results: Twenty-four patients with ATTR-CA were included. Ten (41.7%) patients showed some PYP uptake in the subcutaneous abdominal fat (positive PYP group), and 14 patients did not (negative PYP group). Amyloid deposits were detected by subcutaneous abdominal fat FNAB in 7/10 patients (70.0%) of the positive PYP group versus 0/14 patients (0%) of the negative PYP group, and the difference was significant., Conclusions: In patients with ATTR-CA, abnormal PYP uptake in the subcutaneous abdominal fat could reflect the regional amyloid deposition confirmed by FNAB of this tissue., (© 2021. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Background: Cardiac amyloidosis (CA) mimics left ventricular hypertrophy (LVH). It is treatable, but its prognosis is poor. A simple screening tool for CA would be valuable. CA is more precisely diagnosed with echocardiographic deformation parameters (e.g., relative apical sparing pattern [RASP]) than with conventional parameters. We aimed to 1) investigate incremental benefits of echocardiographic deformation parameters over established parameters for CA screening; 2) determine the resultant risk score for CA screening; and 3) externally validate the score in LVH patients., Methods: We retrospectively studied 295 consecutive non-ischemic LVH patients who underwent detailed diagnostic tests. CA was diagnosed with biopsy or 99m Tc-PYP scintigraphy. The base model comprised age (≥65 years [men], ≥70 years [women]), low voltage on the electrocardiogram, and posterior wall thickness ≥ 14 mm in reference to the literature. The incremental benefit of each binarized echocardiographic parameter over the base model was assessed using receiver operating characteristic curve analysis and comparisons of the area under the curve (AUC)., Results: Fifty-four (18%) patients had CA. RASP showed the most incremental benefit for CA screening over the base model. After conducting multiple logistic regression analysis for CA screening using four variables (RASP and base model components), a score was determined (range, 0-4 points). The score demonstrated adequate discrimination ability for CA (AUC = 0.86). This result was confirmed in another validation cohort (178 patients, AUC = 0.88)., Conclusions: We developed a score incorporating RASP for CA screening. This score is potentially useful in the risk stratification and management of LVH patients., (© 2021. The Author(s).)

Aims: Cardiac amyloidosis (CA) is an infiltrative myocardial disease that occasionally mimics hypertrophic cardiomyopathy (HCM). The aim of this study is to investigate the discriminatory ability of visual assessment of left atrial (LA) function between CA and HCM on echocardiography., Methods and Results: In total, 93 patients with cardiac magnetic resonance imaging (CMR)-confirmed HCM and 34 with cardiac biopsy-confirmed CA were retrospectively assessed. LA dilatation was assessed via echocardiography in an apical four-chamber view. Visual assessment was performed to identify LA dilatation grade (preserved = 1, abnormal = 2, and restricted = 3) based on the extent of outward expansion in the LA reservoir phase. Regarding the reproducibility of visually assessing LA dilatation grade, the kappa values between intra- and inter-observer measurements were 0.82 and 0.70, respectively. Of 127 participants, 57 (45%), 42 (33%), and 28 (22%) presented with LA dilatation Grades 1, 2, and 3, respectively. All 57 patients with preserved LA dilatation (Grade 1) had HCM, and 20 of 28 patients (71%) with restricted LA dilatation (Grade 3) presented with CA. Patients with CA had a higher LA dilatation grade than those with HCM (P < 0.01). LA emptying fraction and reservoir strain were also quantitatively evaluated. The area under the curves of LA dilatation grade (0.88) and LA emptying fraction (0.88) for differentiation of these two diseases were higher than that of LA reservoir strain (0.73) (P < 0.01, respectively). During follow-up, nine patients with HCM and 16 with CA experienced cardiac event (cardiac death or hospitalization due to heart failure). In Kaplan-Meier analysis including both groups of HCM and CA, the incidence of cardiac events was higher in patients with restricted LA dilatation than in those with preserved or abnormal LA dilatation (log-rank test, P < 0.01)., Conclusions: Restricted LA dilatation is an indicator for the diagnosis of CA. Further, visual assessment of abnormal LA motion may facilitate diagnosis in patients with CA and high-risk patients with HCM., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Backgrounds: The relative apical sparing pattern (RASP) of left ventricular (LV) longitudinal strain (LS) is frequently associated with cardiac amyloidosis (CA). However, the visual assessment of RASP is inconsistent, and the quantitative assessment of RASP is time-consuming. This study aimed to compare assessments of RASP for the identification of CA with conventional assessments and investigate their reproducibility and relevance on the assessments., Methods: Forty patients with biopsy-proven CA were compared with 80 hypertrophied patients matched for mean LV wall thickness. We compared the discriminative abilities of three assessments of RASP to identify CA (visual, quantitative, and semiquantitative). Nine patterns of semiquantitative RASP were investigated; finally, it was defined as "reduction of LS" (≥ -10%) in ≥5 (of 6) basal segments, relative to "preserved LS" (< -15%) in at least one apical segment., Results: The concordance between the two observers for visual RASP was modest (κ = 0.65). On the other hand, the consistency for semiquantitative RASP was perfect (κ = 1.00). The discriminative ability of semiquantitative RASP (area under the curve [AUC]  = 0.74) was significantly better than that of visual RASP (AUC = 0.65) and equivalent to that of binary quantitative RASP., Conclusion: Semiquantitative RASP assessment is reproducible and accurately discriminates CA. This simple assessment may help readily refine the risk stratification of patients with diffuse LV hypertrophy., (© 2020 Wiley Periodicals LLC.)

Familial Mediterranean fever (FMF) is a well-known cause of secondary AA amyloidosis. Colchicine is generally considered to be the most effective treatment for FMF and FMF-associated amyloidosis, but the management of patients who are refractory to colchicine remains controversial. We encountered a 51-year-old Japanese man with suspected FMF, who had periodic fever with abdominal pain, polyarthritis, and nephropathy (serum creatinine of 1.9 mg/dL and 24-h protein excretion of 3.8 g). FMF was diagnosed by mutation analysis of the Mediterranean fever (MEFV) gene, which revealed that the patient was compound heterozygous for the marenostrin/pyrin variant E148Q/M694I. AA amyloidosis was diagnosed by renal and gastric biopsy. Colchicine was administered, but his arthritis persisted, and serum creatinine increased to 2.4 mg/dL. Therefore, a humanized anti-interleukin-6 receptor antibody (tocilizumab) was administered at a dose of 8 mg/kg on a monthly basis. Both arthritis and abdominal pain subsided rapidly, and C-reactive protein (CRP) decreased from 2.5 to 0.0 mg/dL. After 2 years, his serum creatinine was decreased to 1.5 mg/dL and proteinuria was improved to 0.3 g daily. In addition, repeat gastric biopsy showed a marked decrease of AA amyloidosis. This case suggests that tocilizumab could be a new therapeutic option for patients with FMF-associated AA amyloidosis if colchicine is not effective.

Background: Systemic wild-type ATTR (ATTRwt) amyloidosis is a prevalent aging-related disorder. However, a limited number of systemic ATTRwt amyloidosis patients have been diagnosed antemortem, and therefore, the prevalence of ATTRwt is underestimated. Here, we investigated clinical findings of a series of systemic ATTRwt amyloidosis patients with antemortem diagnosis., Methods: Thirty-one consecutive patients diagnosed with systemic ATTRwt amyloidosis at Shinshu University Hospital were included in this study. Systemic ATTRwt amyloidosis was diagnosed based on proven ATTR amyloid deposition in biopsy specimens and confirmation of wild-type TTR genotype., Results: The systemic ATTRwt amyloidosis patients consisted of 24 men and seven women, and mean age of onset was 69.8 ± 9.0 years. The most common initial symptom was carpal tunnel syndrome (CTS, 17 patients), followed by heart failure symptoms (14 patients). The mean age at diagnosis was 74.5 ± 8.3 years and the duration of illness from onset to diagnosis was 5.4 ± 4.4 years. Cardiogenic embolism and renal dysfunction are also frequently seen during the course of the disease., Conclusions: CTS is the most common initial symptom of systemic ATTRwt amyloidosis. Our results suggest the possibility of systemic ATTRwt amyloidosis diagnosis at an early stage by carefully examining patients with CTS.

Systemic light chain (AL) amyloidosis is caused by abnormal plasma cell clones producing amyloidogenic light chains. The standard treatment is therefore chemotherapy targeting these clones, however, some patients are ineligible due to liver dysfunction. For these patients, preceding liver transplantation (LT) and following chemotherapy is a possible treatment option. We herein report a 58-year-old man with advanced hepatic AL amyloidosis who was successfully treated using this strategy. Previously reported cases treated with LT for this condition were reviewed, however, the outcomes were not favorable. We additionally investigated potential prognostic factors of this treatment approach to improve the outcome of these patients.

Cardiac amyloidosis is a cardiomyopathy characterized by increased left ventricular (LV) wall thickness and normal or decreased LV cavity size. Congestive heart failure in cardiac amyloidosis is generally considered a predominantly diastolic phenomenon, with systolic dysfunction only occurring in late-stage disease. Echocardiography is a noninvasive, reproducible method of assessing cardiac features and function in cardiac amyloidosis, and some echocardiographic indices are prognostic for the amyloidoses, with M-mode and 2-dimensional echocardiography able to detect increased LV wall thickness. Moreover, Doppler flow measurements can incrementally assess diastolic LV dysfunction, which is characteristic of cardiac amyloidosis, and provide important prognostic information. Additionally, tissue Doppler imaging can detect subtle changes in both systolic and diastolic LV function, which cannot be detected by Doppler flow measurements, and LV longitudinal strain assessed by color tissue Doppler and speckle tracking echocardiography can provide more accurate LV functional and prognostic information than tissue Doppler imaging. This review describes the advances in echocardiography and its crucial role in the diagnosis and management of cardiac amyloidosis.

Amyloidosis refers to disorders that cause organ failure due to amyloid deposition. Deposited amyloid is clearly stained by Congo red and is detected by apple-green birefringence under polarized light. Amyloid fibril proteins are very stable, but several recent studies have revealed that amyloid deposition and the clearance of fibrils cause the steady turnover of deposited amyloid proteins. Therefore, in several amyloidosis disorders, especially primary AL, reactive AA, and transthyretin-related amyloidosis, effective therapies are expected to cause the regression of tissue-deposited amyloid.

Objective: To retrospectively investigate the clinical manifestations at diagnosis in Japanese patients with systemic AL amyloidosis., Methods: We reviewed the medical records of 230 Japanese patients who had visited our hospital and been diagnosed with AL amyloidosis, and abstracted those with the systemic type. The clinical data at diagnosis of systemic AL amyloidosis, including laboratory and imaging findings, were analyzed., Results: Two hundred and two patients (mean, 58.7±9.5 years) were enrolled in this study. Immunofixation or immunoelectrophoresis was performed in 173 patients, 144 of whom were positive for M-protein in the serum and/or urine (κ:λ=30:114). The primary clinical manifestations at diagnosis were proteinuria and/or renal dysfunction (54.0%), congestive heart failure (24.8%), peripheral neuropathy (10.4%), hepatomegaly (7.9%) and arrhythmia (5.0%). The remaining patients developed unusual manifestations, such as solitary tumor, lymphadenopathy, gastrointestinal bleeding, intestinal pseudoobstruction, hemorrhagic tendencies and polyarthralgia. Dilatation of the intestine with marked thickening of the gastrointestinal wall on computed tomography and multiple nodular lesions with associated mucosal friability on endoscopy are characteristic findings of systemic AL amyloidosis., Conclusion: The clinical pictures of Japanese patients with systemic AL amyloidosis are similar to those previously reported from the US and European nations; however, some patients with this disease develop uncommon symptoms. Conducting laboratory and histological examinations for systemic AL amyloidosis is necessary when making a differential diagnosis of these symptoms.

A 52-year-old woman with a high serum alkaline phosphatase (ALP) level underwent a liver biopsy, which showed diffuse heavy deposition of Aκ amyloid, and was diagnosed as having immunoglobulin light chain (AL) amyloidosis. Although she received high-dose melphalan with stem cell transplantation and achieved a hematologic complete response (CR), her ALP level began to increase one year after treatment. Further examinations revealed that she was still in a CR state with dominant bone-type ALP, and re-biopsied liver specimens demonstrated marked regression of amyliod deposition, providing important evidence that the turnover of hepatic amyloid proteins can actually occur more rapidly than previously thought.

Objective: To investigate histological features of deposited amyloid in the synovial tissue and its clinical significance in knee joint osteoarthritis (OA) patients., Methods: We prospectively enrolled 232 consecutive patients who underwent arthroplasty or total replacement of the knee joint for treatment of OA. Congo red staining and immunohistochemistry were performed in the synovial tissue obtained at surgery. When transthyretin (TTR)-derived amyloid was positive, we analyzed all 4 exons of the TTR gene using the direct DNA sequencing method in order to detect mutations., Results: We analyzed 322 specimens in this study. Twenty-six specimens (8.1%) obtained from 21 patients (5 men and 16 women; mean, 79.0 ± 4.6 years) showed deposition of amyloid, which was positively stained with the anti-TTR antibody. Eighteen patients showed inhomogeneous accumulations of amyloid in the loose connective tissue under the synovial epithelia sometimes with nodule formation, while in the remaining three, small vessels in the adipose tissue were involved. Medical records of these patients revealed nothing remarkable in the clinical course, laboratory data or macroscopic intraarticular findings at surgery. No mutations were detectable in the TTR gene analysis., Conclusion: Wild-type TTR-derived amyloid may affect the synovial tissue as a result of long-term mechanical stress or as a part of senile systemic amyloidosis in approximately 8% of knee joint OA patients. No obvious clinical significance was found in synovial deposition of amyloid.

The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIIIth International Symposium, May 6-10, 2012, Groningen, The Netherlands, to formulate recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate amyloid fibril proteins for inclusion in the ISA Amyloid Fibril Protein Nomenclature List. The need to promote utilization of consistent and up to date terminology for both fibril chemistry and clinical classification of the resultant disease syndrome was emphasized. Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. Although the importance of fibril chemistry to the disease process has been recognized for more than 40 years, to this day the literature contains clinical and histochemical designations that were used when the chemical diversity of amyloid diseases was poorly understood. Thus, the continued use of disease classifications such as familial amyloid neuropathy and familial amyloid cardiomyopathy generates confusion. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit both affinity for Congo red and green birefringence when Congo red stained deposits are viewed by polarization microscopy. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when so is practically possible. Thus, in nearly all cases, it is insufficient to demonstrate mutation in the gene of a candidate amyloid protein; the protein itself must be identified as an amyloid fibril protein. Current ISA Amyloid Fibril Protein Nomenclature Lists of 30 human and 10 animal fibril proteins are provided together with a list of inclusion bodies that, although intracellular, exhibit some or all of the properties of the mainly extracellular amyloid fibrils.

We describe a rare complication, systemic arterial thromboembolism, seen in two patients with senile systemic amyloidosis (SSA). Case 1 was a 73-year-old man who was tentatively diagnosed as having cardiac amyloidosis. Five months later, he was afflicted by severe left flank pain. CT disclosed renal infarction and then he received endomyocardial biopsy and the transthyretin (TTR) gene analysis, leading to the final diagnosis of SSA. Case 2 was an 88-year-old woman who had been definitively diagnosed as having SSA-related heart failure with atrial fibrillation two years before. She was transferred to the emergency room in our hospital and enhanced CT revealed complete occlusions of the left internal carotid and left vertebral arteries, both subclavian arteries, and the left renal and left internal iliac arteries. Paying much attention to intracardiac thrombosis might be necessary in taking care of SSA patients.

Common neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are now considered as "protein misfolding diseases," because the misfolding of a small number of proteins is a key event in the pathogenesis and progression of these diseases. Proteins that are prone to misfolding and thereby associated with neurodegenerative diseases include amyloid β (AD), tau (AD and tauopathy), α-synuclein (PD, dementia with Lewy bodies, etc.), polyglutamine proteins (Huntington's disease, spinocerebellar ataxia, etc.), and superoxide dismutase 1 (amyotrophic lateral sclerosis). These proteins share certain essential properties with prions. Similar to abnormal prions, misfolded proteins function as a template to catalyze the misfolding of the native proteins and assemble into insoluble, β-sheet-rich, fibrillar aggregates termed as "amyloids." Furthermore, there is enough evidence supporting the intercellular transfer of misfolded protein aggregates. The transmission of these aggregates from one cell to another may be in accordance with the concept that neuropathological changes propagate along neuronal circuits in neurodegenerative diseases. Prion-like propagation mechanisms have been extensively analyzed in connection with systemic amyloidoses such as amyloid A (AA) amyloidosis and amyloid apolipoprotein AII (AApoAII) amyloidosis. Studies have shown that AA and AApoAII amyloidoses are transmitted from one organism to another through amyloid fibrils. However, studies have not yet proved that protein misfolding diseases, except for prion diseases, are infectious. Given the intercellular transfer of misfolded protein aggregates, we cannot ignore the possibility that disease-specific, misfolded proteins can be transmitted between individuals through surgical procedures or tissue transplantation. Importantly, cell non-autonomous mechanisms underlying the pathogenesis of neurodegenerative diseases may represent a more readily accessible target for novel disease-modifying therapies. In the present review, we discuss some aspects of the prion-like propagation of neurodegenerative diseases, taking into consideration the accumulated evidence supporting the transmissibility of systemic amyloidoses.

Senile systemic amyloidosis (SSA) is a main cause of intractable heart failure in elderly individuals. To demonstrate transthyretin (TTR)-derived amyloid deposition endomyocardial biopsy has been commonly carried out in the patients with SSA, but this invasive biopsy technique cannot always be performed in aged patients with severe cardiac dysfunction. During the past 3 years, 11 patients with SSA (6 males and 5 females; ages from 70 to 97 years) were examined. All underwent skin biopsy from the abdominal wall and 8 showed TTR-immunoreactive amyloid deposition (sensitivity: 73%): amyloid deposits were seen mainly in the deep layer of subcutaneous fat tissue and showed a patchy distribution. They were weakly Congophilic, but were strongly immunolabeled by an anti-TTR antibody. The severity and pattern of amyloid deposition in this biopsy of SSA patients were considerably different from those obtained from age-matched patients with TTR-related familial amyloid polyneuropathy. Surgical skin biopsy including the deep subcutaneous fat pad can be performed safely at the bedside and is useful for the histopathological diagnosis of SSA.

Systemic amyloidosis that includes familial transthyretin (TTR)-related amyloid polyneuropathy (FAP) and primary systemic immunoglobulin light chain (AL)-derived amyloidosis was long considered to be an incurable disease, but effective therapeutic approaches developed during 20 years ago: liver transplantation for FAP and high dose melphalan with autologous peripheral blood stem cell transplantation (Auto-PBSCT). Systemic amyloidosis is characterized by the presence of an amyloid precursor protein in serum and both treatments can cease the production of amyloid precursor proteins in serum. After transplantation the progression of FAP symptoms certainly stopped, and the patients who were in an early stage of the disease and underwent successful operation showed considerable improvement in their quality of life. Similar clinical recovery was seen in primary systemic AL amyloidosis patients with polyneuropathy after high dose melphalan with auto-PBSCT. Histopathological regression of amyloid deposits on aspirated abdominal fat tissues and/or gastroduodenal mucosa was demonstrated in the patients with long post-treatment courses, indicating that an amyloid precursor protein is dynamically turned over in the lesions with amyloid deposits.

Wild-type transthyretin is inherently an amyloidogenic protein, but its contribution to the formation of amyloid fibrils remains unclear in familial amyloid polyneuropathy patients. Our aim in this study was to elucidate the ratio of wild-type transthyretin in amyloid deposits in familial amyloid polyneuropathy patients. Abdominal fat amyloid fibrils in 44 familial amyloid polyneuropathy patients with amyloidogenic transthyretin Val30Met who had not undergone liver transplantation were examined. The amyloid fibrils were extracted from abdominal fat tissues and the composition ratios of wild-type and variant transthyretin were analyzed with liquid chromatography tandem mass spectrometry. The amyloid fibrils in abdominal fat tissues were composed of not only variant but also wild-type transthyretin in most patients (mean ratio, 40.7% ± 27.5%). The composition ratios of wild-type transthyretin in patients older than 50 years were significantly higher than those in patients younger than 50 (50.7% ± 26.9% versus 30.7 ± 24.8%). Our results indicate that wild-type transthyretin significantly contributes to the formation of amyloid fibrils in familial amyloid polyneuropathy patients with amyloidogenic transthyretin Val30Met, and its contribution tends to increase in older patients, suggesting that aging may play an important role in wild-type transthyretin-derived amyloid fibril formation in familial amyloid polyneuropathy patients. This is the first report showing the relationship between wild-type transthyretin deposition and aging in familial amyloid polyneuropathy patients. In addition, wild-type transthyretin may be more strongly amyloidogenic than previously considered because it is detectable even in amyloid fibrils isolated from young familial amyloid polyneuropathy patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Systemic reactive amyloid A (AA) amyloidosis is one of the critical complications associated with rheumatoid arthritis (RA). Recently, there are several useful reports of anti-tumor necrosis factor therapy for RA-related systemic reactive AA amyloidosis patients. However, the time-kinetic transition between effective anti-inflammatory therapies and regression of AA amyloid deposits remains uncertain. Here, we report a RA patient with systemic reactive AA amyloidosis who was successfully treated with prednisolone and etanercept, showing marked regression of gastroduodenal mucosal amyloid deposits within only 4 months. This is the first case report of RA-related systemic reactive AA amyloidosis histopathologically demonstrating rapid regression of amyloid deposits on gastroduodenal mucosa after adequate suppression of the underlying inflammatory condition.

A 60-year-old woman was found to have proteinuria and a lung nodule. The surgically resected left upper lobe contained a nodule, in which the adenocarcinoma was surrounded by a heavy deposition of amyloid. Subsequent renal and gastric biopsies demonstrated amyloid deposition with Aλ immunoreactivity. She was treated with 2 courses of VAD (vincristine, doxorubicin and dexamethasone), resulting in the disappearance of Bence Jones proteinuria. Her nephrotic syndrome has been improving during the subsequent 3 years. The rare lung nodule consisting of adenocarcinoma and amyloid deposition was a diagnostic clue in this primary systemic AL amyloidosis patient.

A system of amyloid fibril nomenclature based on the chemical identity of the amyloid fibril forming protein is recommended. This system has been in use for approximately 40 years, but current literature remains confused with clinical and histochemical designations used when the amyloid disease processes were poorly understood. To be designated an amyloid fibril protein, the protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarisation microscopy. Furthermore, the protein must have been unambiguously characterised by protein sequence analysis (DNA sequencing in the case of familial diseases). Current nomenclature lists of 27 human and nine animal fibril proteins are provided together with a list of eight inclusion bodies that exhibit some of the properties of amyloid fibrils.

Senile systemic amyloidosis (SSA) is a rather common disease in elderly people, but it is very rare in animals, including nonhuman primates. Pathological examination of a 26-year-old male savannah monkey (Cercopithecus aethiops) revealed systemic amyloidosis with severe cardiac fibrosis, and tenosynovial degeneration of the elbow and knee joints. The amyloid deposits were observed predominantly in the heart, lung, intestine and tenosynovium, and were positive for transthyretin (TTR) in immunohistochemistry. Immunohistochemical results, together with the distribution of the amyloid deposited lesions and the age of the monkey, were equivalent to those of human SSA. This is the second case of animal SSA with unprecedented TTR amyloid deposited lesions of the tenosynovium resembling human SSA. There may be a genetic factor that makes this species susceptible to SSA, since SSA has been reported in no other mammal besides humans.

It has been shown that experimental murine AA amyloidosis can be enhanced by dietary ingestion of amyloid fibrils, and it is known that systemic AA amyloidosis occasionally develops in aged cattle. In this study, we examined amyloid deposits in renal and muscular tissues simultaneously obtained from slaughtered aged cattle; from both tissues when affected, amyloid-enhancing activity was also investigated. On histopathology, renal amyloid deposition was seen in nine of the 293 cattle with no history of disease, and minute amyloid deposition in muscular tissue was detectable in one of these nine. All these amyloid deposits were immunohistochemically demonstrated to be AA. Extracts, which might contain amyloid fibril fractions, were isolated from renal and muscular tissues in five of these nine cattle. On SDS-PAGE and Western blot analysis, protein bands immunoreactive to anti-AA serum were detected in the kidney fractions obtained from four of the five latter cattle, but no bands were seen in the muscle fractions of any of the five cattle. Amyloid fibril fractions from two cattle were intravenously injected into group of seven experimentally designed mice for induction of AA amyloidosis. All seven mice injected with kidney fraction developed severe AA amyloidosis, whereas only one of the seven mice given muscle fraction showed slight amyloid deposition in the spleen. These data suggest that food products made from aged cattle possess amyloid-enhancing potential.

We report a 67-year-old male patient who suffered from nephrotic syndrome and progressive renal dysfunction with monoclonal gammopathy (IgMkappa). Renal biopsy demonstrated amyloid deposition in glomeruli. Immunohistochemical studies of the renal amyloid using a number of antibodies, including anti-lambda and anti-kappa light chains, AA, beta(2)-microglobulin, and transthyretin, showed negative findings. Biochemical analysis of the deposited amyloid fibrils in gastroduodenal mucosa revealed that the amyloid fibrils were composed of an immunoglobulin heavy chain variable region (VH) fragment belonging to the VH1 subgroup, and a diagnosis of AH amyloidosis was made. In our institute, three patients with AH amyloidosis including the present one have been identified during the past 2 years, so AH amyloidosis seems to be by no means a rare disorder.

We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. Two of the patients were considered to be classifiable as primary systemic AL amyloidosis based on the presence of M-protein in serum and abnormal plasma cells or lymphoplasmacytoid cells in the bone marrow probably producing the precursor immunoglobulin, although no visceral organs were affected. The size of the involved lymph nodes in these two patients increased gradually, and one was treated with rituximab and VAD (vincristine, doxorubicin and dexamethasone) followed by high-dose melphalan with autologous peripheral blood stem cell transplantation (auto-PBSCT). The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.

Senile systemic amyloidosis (SSA) is caused by the deposition of wild-type transthyretin (TTR)-derived amyloid fibrils. This type of amyloidosis is not rare in elderly individuals over the age of 80 and is usually detected on postmortem microscopic examination of myocardium. We report a 67-year-old male patient who was clinically diagnosed as having SSA with cardiac involvement. The initial event was cerebral infarction conceivably due to cardiac embolism. Endomyocardial biopsy was performed twice, which led to a definitive diagnosis of amyloidosis at the second biopsy. This amyloid was immunolabeled by an anti-TTR antibody and direct DNA sequencing of the TTR gene did not detect any mutation. Clinical confirmation of SSA in individuals before the age of 70 is infrequent and cardiac amyloidosis associated with this disease might have been the cause of cerebral embolism in our patient. Additionally, it is important to distinguish cardiac amyloidosis of SSA from that of primary immunoglobulin light chain (AL)-derived amyloidosis, because the treatment and prognosis differ considerably from those of primary AL amyloidosis.

Systemic amyloidosis is characterized by the involvement of multiple organs and the presence of an amyloid precursor protein in serum. This disorder is classified into four major forms: immunoglobulin light chain-derived (AL), reactive AA, dialysis-related (beta2M) and hereditary transthyretin (ATTR) type. Heart, kidney, gastrointestinal tract and peripheral nerves are commonly affected by amyloid deposition in systemic amyloidosis and histopathological demonstration of amyloid deposits on any of affected organs is the first step leading to the diagnosis of this disease. Immunohistochemical analysis of amyloid protein on tissue amyloid deposits is necessary to make classification of the disease and DNA testing is also useful in a hereditary form. Amyloidosis had been considered to be an incurable disease but during the past one decade several therapeutic approaches have been employed for the amyloidosis patients with diverse pathogenetic backgrounds: intravenous large dose of melphalan accompanied by autologous peripheral blood stem cell transplantation for AL amyloidosis and liver transplantation for hereditary ATTR type amyloidosis. As a result some amyloidosis patients have been rescued and are now enjoying their own social lives. It is likely that recent advance on the research of amyloidosis has changed the concept of this disease.

We report 3 patients with nephrotic syndrome ascribed to primary systemic AL amyloidosis that were successfully treated with VAD (vincristine, doxorubicin and dexamethasone) alone. M-protein in serum disappeared soon after VAD, and nephrotic syndrome gradually improved in parallel with a decrease in daily protein excretion in urine. Long-term follow-up of these patients showed neither relapse of nephrotic syndrome nor reappearance of M-protein. High-dose melphalan followed by autologous stem cell support is a standard therapy for primary systemic AL amyloidosis, but in high-risk cases for this treatment, such as elderly patients and those with multiple organ involvement, VAD might be a therapeutic option.

We report a patient with myeloma-associated systemic AL amyloidosis who showed chronic polyarthralgia as the main symptom. The clinical picture was similar to that of rheumatoid arthritis with regard to symmetrical swelling with tenderness in multiple joints, but inflammatory reactions were almost normal and autoantibodies were negative. He was diagnosed as having systemic AL amyloidosis based on deposition of kappa-light chain-immunoreactive amyloid in biopsied tissue and Bence Jones protein in serum and urine. Magnetic resonance imaging and bone scintigraphy suggested this disease as the cause of the polyarthralgia. Systemic AL amyloidosis may be important in the differential diagnosis of chronic polyarthralgia.

Objective: Intensive chemotherapy targeting plasma cell dyscrasia has been recently employed for the treatment of primary systemic AL amyloidosis. We prospectively studied the clinical usefulness of cyclic VAD (vincristine, doxorubicin and dexamethasone) in patients with primary systemic AL amyloidosis who were ineligible for high-dose melphalan with autologous stem cell support., Patients and Methods: Eight patients (mean age, 60.4+/-8.8 years) were treated with cyclic VAD until the disappearance of M-protein from both serum and urine. Of these, seven showed nephrotic syndrome before the start of VAD irrespective of a decrease in creatinine clearance. Serial follow-up studies after VAD evaluated hematological status and organ function., Results: Four patients (50%) showed a marked decrease in abnormal plasma cells in the bone marrow and normalized kappa/lambda ratios of serum free light chain in conjunction with disappearance of M-protein after 1 to 3 courses of VAD. There were no serious adverse events, and nephrotic syndrome gradually improved with no hematological relapse in the follow-up period of 3 to 5 years. The remaining 4 patients showed worsening of congestive heart failure and/or systemic edema ascribable to dexamethasone, resulting in cessation of cyclic VAD before disappearance of M-protein. All of these patients died of multiple organ failure or required permanent hemodialysis within 1 year after the start of cyclic VAD., Conclusion: Cyclic VAD is a potent therapeutic option in primary systemic AL amyloidosis, but in patients with renal or cardiac dysfunction careful management for adverse events, especially body fluid retention, is necessary.

Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials.

Objective: Primary systemic AL amyloidosis arises from immunoglobulin light chains produced by plasma cell dyscrasia. To prospectively investigate the production of M-protein and plasma cells in bone marrow before and after chemotherapy, we performed flow cytometry and analysis of serum free light chains (FLCs)., Patients and Methods: Fifty-nine patients with primary systemic AL amyloidosis (mean age, 59.9+/-8.8 years) were enrolled in this study, and of these 31 were serially studied before and after chemotherapy. Complete hematological remission was defined as normalization of the FLC kappa/lambda ratio., Results: MPC-1(-)CD45(-) (p<0.05) and MPC-1(+)CD45(-)CD49e(-) (p<0.005) were significantly higher, and MPC-1(-)-CD45(+) (p<0.05), MPC-1(+)CD45(+)CD49e(-) (p<0.0001) and MPC-1(+)CD45(+)CD49e(+) (p<0.0005) were significantly lower in the patients with AL amyloidosis than in controls. There was a significantly positive correlation between the serum predominant FLC/serum creatinine ratio and MPC-1(+)CD45(-)CD49e(-) (p<0.05). After chemotherapies, such as high-dose melphalan with autologous stem cell support, 20 of 31 patients with AL amyloidosis achieved complete hematological remission. There were no significant differences in any subtype of plasma cells before treatment between the remission and non-remission groups, but in the former group MPC-1(+)CD45(-)CD49e(-) and MPC-1(-)CD45(+) were significantly decreased and increased after chemotherapy compared with before, respectively., Conclusion: Abnormal plasma cells in the bone marrow, particularly the MPC-1(+)CD45(-)CD49e(-) subset, may be important as a follow-up marker before and after chemotherapy in primary systemic AL amyloidosis. These cells maintain low levels as long as no relapse occurs.

The increasing knowledge of the exact biochemical nature of the localized and systemic amyloid disorders has made a logical and easily understood nomenclature absolutely necessary. Such a nomenclature, biochemically based, has been used for several years but the current literature is still mixed up with many clinical and histochemically based designations from the time when amyloid in general was poorly understood. All amyloid types are today preferably named by their major fibril protein. This makes a simple and rational nomenclature for the increasing number of amyloid disorders known in humans and animals.