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We describe a patient with amyloidosis of renal pelvis and 2 patients with urinary bladder amyloidosis. Clinical presentation in all of the cases mimicked cancer of the respective sites. Clinical diagnosis of amyloidosis is not possible, making biopsy mandatory. Immunology of amyloid formation and treatment of amyloidosis are discussed.
Localised alveolar-septal amyloidosis has been thought irreversible. A woman exposed to the dust of sea-snail shells during the manufacture of nacre buttons had clinical and immunological features typical of hypersensitivity pneumonitis; however, transbronchial lung biopsy showed alveolar-septal amyloidosis. There was no evidence of other diseases known to be associated with amyloidosis, nor were amyloid deposits found in other organs. After a year without exposure to the antigen there was no trace of either pneumonitis or amyloidosis.
In the present study, we report our extended data on the incidence of two types of cerebral amyloidosis (plaques and plaques associated with angiopathy) and visceral amyloidosis in late adult and aged captive rhesus monkeys (Macaca mulatta). In a total of 81 brains from animals ranging from 16 to 39 years old, beta-amyloid plaques were found in 38, 10 of which were associated with amyloid angiopathy. Brains from eight adults, 16 to 19 years, had no lesions. In aged groups, the rates were 20.8% in the 20- to 25-year group (24), 60.9% in the 26- to 31-year group (41), and 100% in the 33- to 39-year group (8). Twelve monkeys in these aged groups had an involvement of amyloidosis in either the liver, the adrenal, or the pancreatic islets, and 7 of 12 had amyloid plaques (5) and plaques associated with cerebral angiopathy (2). No neurofibrillary tangles were detected in these brain lesions. Amyloid in both plaques and cerebral angiopathy showed immunocytochemical crossreactivity with human amyloid beta (beta/A4) and precursor proteins (APP-A4), but visceral amyloid was negative. Ultrastructurally, amyloid initially appears as loose filaments in the perivascular or Disse space, and they further aggregate to produce dense interlacing bundles. Cerebral amyloid angiopathy associated with plaque appears to be a subclass of senile plaque lesions in aged monkeys as well as in aged humans, and it appears to have no pathogenetic correlation with visceral amyloidosis.
Primary systemic amyloidosis rarely affects the walls of small and medium-sized vessels. We report a case of primary AL amyloidosis masquerading as giant cell arteritis at the onset of the disease, revealed by the temporal arteritis biopsy, and successfully treated by corticotherapy for three years. Histology of temporal arteritis confirms the diagnosis of amyloidosis (characteristic birefringence with Congo red). We discuss in this case the diagnosis of primary amyloidosis revealed by Horton disease, or the coincidental association of these two diseases.
The clinical amyloidosis syndromes are a heterogeneous group of disorders characterised by abnormal extracellular accumulation of autologous protein material. Amyloid deposits are largely composed of insoluble protein fibrils which are intimately associated with sulphated glycosaminoglycan residues. Amyloid P component (AP) is a minor but almost universal constituent of the deposits and is derived from the normal circulating glycoprotein serum amyloid P component (SAP), a member of the pentraxin family of plasma proteins. The current classification of amyloidosis is based on the chemical nature of the fibril protein subunits. Systemic amyloidosis is well known as a relatively rare but important cause of serious morbidity, and vital organ involvement is usually fatal. In recent years it has become increasingly recognised that amyloid deposition in a variety of sites is a universal feature of ageing, and in particular that amyloid in the cerebral blood vessels and within the brain itself is an integral part of the pathology of Alzheimer's disease. Also recently, a new form of amyloid has emerged, confined to patients who have received long term haemodialysis for end stage renal failure, in whom beta 2-microglobulin (beta 2M) is laid down as amyloid fibrils predominantly in periarticular and bony tissues. Considerable progress in knowledge of the composition, molecular structure and properties of many different constituents of amyloid has been made in the past 30 years. However, the precise mechanisms of amyloid fibril formation, deposition and persistence are not known and no generally effective therapy yet exists which can arrest amyloid deposition or promote its resolution. A major reason for our ignorance of the natural history of amyloidosis is that it is an exclusively histological diagnosis, at the time of which most patients with systemic disease have extensive amyloid deposits throughout many organs and a very poor prognosis. Some optimism has been generated from recent work suggesting that amyloid fibrils are not inherently non-biodegradable and that the use of radiolabelled SAP may permit non-invasive sensitive, scintigraphic imaging of amyloid deposits in vivo.
Twenty-six non-randomized patients with carpal tunnel syndrome are presented. It is documented that three out of four patients may be diagnosed pre-operatively by five or more clinical parameters. All patients were screened for amyloidosis in biopsies from the carpal tunnel. One patient presented amyloid deposits in the transversal carpal ligament. The importance of macro- and microscopic findings in the carpal tunnel inclusive local amyloidosis for the pathogenesis of the carpal tunnel is discussed. It is concluded that provided systemic amyloidosis is not suspected, screening for amyloidosis may have diagnostic interest, however without therapeutic consequences and therefore unnecessary.
This study sought to determine plasma levels of B-natriuretic peptide (BNP) in patients with light-chain-associated amyloidosis and correlate them with the presence or absence of heart failure (HF) and the presence or absence of echocardiographic abnormalities. Patients with normal echocardiographic results had significantly lower BNP levels than those with echocardiographic features of cardiac amyloidosis, whereas BNP levels in the group with HF did not differ from those in patients with asymptomatic cardiac amyloidosis. This observation supports previous observations, suggesting that the elevation of BNP in cardiac amyloidosis may be due not only to elevated ventricular filling pressure but also to direct myocyte damage due to extracellular deposits of amyloid.
Primary intrapulmonary nodular amyloidosis is a rare form of immunoglobulin associated amyloidosis, also falling under the alternative appellation of amyloidoma. Although amyloidomas in other organ sites may be reflective of a localized or more generalized plasma cell dyscrasia, in the context of its presentation in the lung the presumptive basis has long been held to be one of chronic inflammation. We encountered 2 patients with nodular amyloidosis in whom the pathologic examination disclosed the basis to be one of a light chain restricted clonal lymphocytic plasma cell infiltrate, although without morphologic features of coexisting pulmonary lymphoma. These 2 patients serve to underscore the potential categorization of some cases of pulmonary nodular amyloidosis as a form of low grade B cell lymphoproliferative disease.
Amyloidosis remains a severe potential complication of many chronic inflammatory disorders, foremost of rheumatoid arthritis. It is not exactly known why some patients develop a progressive amyloidosis while others do not, although latent deposits may be present. It is likely that more potent anti-inflammatory drugs recently used in rheumatoid arthritis have led to a decrease of amyloid-associated (AA) amyloidosis. However, overt amyloidosis remains a severe complication of some chronic inflammatory disorders and it has a poor prognosis. Hereditary fevers are a group of diseases characterized by intermittent bouts of clinical inflammation with focal organ involvement, mainly abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever which affects patients of Mediterranean descent all over the world. Three other types have been recently characterized clinically as well as genetically. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases.
OBJECTIVE: This study was performed to clarify whether the longitudinal myocardial velocity gradient could give new insights into the features of congestive heart failure in patients with primary amyloidosis. METHODS: A total of 33 consecutive patients with biopsy specimen-proven primary amyloidosis were examined by pulsed Doppler tissue imaging. RESULTS: In all, 22 had evidence of heart involvement, of whom 11 had clinical congestive heart failure. Sample volumes were placed on basal and midventricle in the apical 2- and 4-chamber views. Peak systolic, and peak early and late diastolic wall-motion velocities were measured at each site. Longitudinal myocardial velocity gradients were calculated as the difference between basal and midmyocardial velocities. Single-point analysis of pulsed Doppler tissue imaging could not distinguish any difference among groups, whereas the longitudinal myocardial velocity gradients in systole and early diastole were significantly impaired in the patients with congestive heart failure compared with both the patients without cardiac involvement and those with cardiac amyloidosis without congestive heart failure. CONCLUSION: Longitudinal myocardial velocity gradient is a sensitive method for detecting systolic and diastolic dysfunction in cardiac amyloidosis and is superior to single-point analysis Doppler tissue imaging.
Dynamic left ventricular outflow tract (LVOT) obstruction is classically seen in hypertrophic obstructive cardiomyopathy (HOCM). This can also be seen in cardiac amyloidosis. We describe a rare case of senile systemic amyloidosis with dynamic LVOT obstruction and concomitant three vessel coronary artery disease presenting with clinical and echocardiographic findings similar to those seen in HOCM. We also highlight the importance of distinguishing the sub-types of amyloidosis so that the appropriate therapy can be offered to patients with cardiac involvement, including coronary artery bypass grafting and septal myotomy/myectomy to relieve LVOT obstruction in the more benign forms of cardiac amyloidosis.
Acquired bleeding abnormalities are common in patients with primary amyloid light-chain amyloidosis. Factor X deficiency is the most common coagulopathy associated with life-threatening hemorrhagic complications when surgery is indicated. Fresh-frozen plasma (FFP) or prothrombin complex concentrates (PCCs) are the most frequently used blood products in this disease; however, FFP is often ineffective in controlling bleeding and PCCs have a significant risk of thrombosis when used intraoperatively. This report describes a patient with primary amyloidosis and factor X deficiency who underwent hemicolectomy with preoperative and intraoperative administration of recombinant human factor VIIa and postoperative administration of Bebulin (a PCC that contains the highest concentration of factor X). The management was successful with no signs of bleeding postoperatively. To our knowledge, few reports of successful perioperative management of factor X deficiency have been published to date. This is the first case report using recombinant human factor VIIa and Bebulin in the perioperative management of factor X deficiency associated with primary amyloidosis. Recombinant human factor VIIa and Bebulin may allow for successful perioperative management of bleeding disorders in patients with primary amyloidosis.
Amyloid-associated protein (AA)-type systemic amyloidosis has been referred to as secondary amyloidosis because it is secondary to an associated inflammatory condition. It is extremely rare in patients with non-Hodgkin's lymphoma (NHL). Here we report an autopsy case of follicular small cleaved cell lymphoma with focal large B-cell lymphoma transformation in association with systemic AA-type amyloidosis. Formalin-fixed, paraffin-embedded tissues from autopsy and the patient's previous surgical specimen were studied by Congo red stain; electron microscopy; and immunostaining with antibodies against AA protein, P component, and kappa and lambda light chains. There was a marked AA amyloid deposition in the glomeruli of both kidneys, the retroperitoneal lymphoma mass, the blood vessels, the adrenal glands, and the adipose tissues. The patient's previous surgical specimens were negative for amyloid. We propose that this patient's systemic AA-type amyloidosis developed along the course of his NHL.
Cardiac involvement is a significant cause of morbidity and mortality in patients with amyloidosis. A 73-year old Caucasian woman was admitted to a hospital with increasing dyspnoea. Examination revealed a large left-sided pleural effusion, gross peripheral oedema and a pan-systolic murmur. The electrocardiogram showed low voltage QRS complexes with lateral T wave inversion. Recent angiography had demonstrated normal coronaries. Echocardiography revealed left ventricular hypertrophy and an ejection fraction of 43%. There was a restrictive filling pattern with elevated left-sided filling pressures, left atrial enlargement and mild mitral regurgitation. The right heart was normal with normal filling pressures. The patient was referred for cardiovascular magnetic resonance imaging for investigation of restrictive cardiomyopathy. This case provides a striking demonstration of the characteristic features of cardiac amyloidosis by cardiovascular magnetic resonance imaging - impaired biventricular systolic function, thickened atrioventricular valves, bi-atrial enlargement, increased atrial septal thickness and left ventricular mass, pleural and pericardial effusions, and the most impressive finding of widespread subendocardial hyperenhancement of both ventricles, as well as the inter-atrial and inter-ventricular septa, representing infiltration with amyloid protein. Cardiac involvement with systemic amyloidosis was suspected and confirmed on biopsy. Cardiovascular magnetic resonance imaging should be considered early in the diagnostic work-up of suspected cardiac amyloidosis.
PURPOSE: To characterize the clinicopathologic phenotype as well as the molecular genetic basis of an autosomal dominant form of corneal amyloidosis. DESIGN: Clinicopathologic and molecular genetic study of a family with a form of corneal amyloidosis. PARTICIPANTS: Forty-nine individuals from one family were studied. METHODS: The medical records of affected family members were reviewed, and corneal tissue from those who had undergone penetrating keratoplasty (PK) was examined. Several family members were examined clinically, and corneas were photographed. Deoxyribonucleic acid from blood or buccal swabs was extracted from each consenting family member to determine the status of their transforming growth factor beta-induced (TGFBI) gene. The coding region of the TGFBI gene was analyzed for mutations in the proband's DNA, and compared with the nucleotide sequences of normal individuals. This was performed by amplifying and sequencing all exons of the TGFBI gene. In all other family members, only exons 4, 8, 11, and 12 of the gene were amplified, sequenced, and analyzed for mutations. MAIN OUTCOME MEASURES: Clinicopathologic manifestations in relation to mutational status of the TGFBI gene. RESULTS: Slit-lamp biomicroscopy revealed bilateral multiple polymorphic, polygonal, refractile, chipped ice-appearing gray and white opacities. There were also occasional deep filamentous lines that did not form a distinct lattice pattern. Corneal tissue of affected individuals who underwent PK contained widespread deposits of amyloid within the corneal stroma, particularly in the deep central stroma. Twelve members of the family were found to have a heterozygous single mutation in the TGFBI gene leading to a predicted amino acid substitution of aspartic acid for alanine (A546D). Nine of these individuals had ophthalmologist-documented corneal disease. The remaining 3, who were 11, 14, and 15 years old, were asymptomatic. In addition, 4 inconsequential polymorphisms with the nucleotide changes 387 G/A (R129R), 981 G/A (V327V), 1416 T/C (L472L), and 1620 C/T (F540F) were found. CONCLUSION: A distinct, progressive form of corneal amyloidosis with an autosomal dominant mode of inheritance is characterized clinically by the presence of refractile polymorphic corneal opacities. We have designated this entity, which is caused by an A546D mutation in the TGFBI gene, polymorphic corneal amyloidosis.
OBJECTIVE: To present the clinical features and management outcome in a large series of patients with periocular and orbital amyloidosis. DESIGN: Retrospective, noncomparative, interventional case series. PATIENTS: All patients diagnosed with periocular and orbital amyloidosis in 6 oculoplastic and orbital units. METHODS: Clinical records of all patients were reviewed. MAIN OUTCOME MEASURES: Clinical presentation, radiological and histological findings, treatment modalities, and outcome. RESULTS: The study included 24 patients (15 female, 9 male) with a mean age of 57+/-17 years. Nineteen cases were unilateral, and 5 were bilateral. Clinical signs and symptoms included a visible or palpable periocular mass or tissue infiltration (95.8%), ptosis (54.2%), periocular discomfort or pain (25%), proptosis or globe displacement (21%), limitations in ocular motility (16.7%), recurrent periocular subcutaneous hemorrhages (12.5%), and diplopia (8.3%). Seven cases had orbital involvement, and 17 were periocular. Immunohistochemistry in 7 patients showed B cells or plasma cells producing monoclonal immunoglobulin chains that were deposited as amyloid light chains. Only 1 patient was diagnosed with systemic amyloid light chain amyloidosis. Treatment modalities were mainly observation and surgical debulking. During a mean follow-up period of 39 months, 21% showed significant progression after treatment, whereas 79% were stable or showed no recurrence after treatment. CONCLUSION: Periocular and orbital amyloidosis may present with a wide spectrum of clinical findings and result in significant ocular morbidity. Complete surgical excision is not feasible in many cases, and the goal of treatment is to preserve function and to prevent sight-threatening complications.
Primary systemic amyloidosis (AL) is a well-recognized systemic disease, and cardiac amyloidosis accounts for 10% of all nonischemic cardiomyopathies [J S C Med Assoc 97 (2001) 201-206]. The median survival of patients with symptomatic congestive heart failure secondary to cardiac amyloidosis is 4 months [New Engl J Med 336 (1997) 1202-1207; Am J Med 100 (1996) 290-298]. The cause of death in most patients is refractory congestive heart failure or sudden arrhythmic [Mayo Clin Proc 59 (1984) 589-597]. While there are reports of in-hospital arrhythmic deaths in these patients, there are no detailed reports that describe the presentation and management of patients with cardiac amyloidosis who have experienced an out-of-hospital cardiac arrest (OHCA). We describe here our experience with four patients with AL who had an OHCA, including presenting rhythms, interventions, and outcomes.
INTRODUCTION: Amyloidosis is a systemic disease. Heart transplantation in this subset of patients is contraindicated by the majority of authors. In our center, patients with heart failure due to amyloidosis have been evaluated for cardiac transplantation since 1991. The aim of this study was to analyze the outcome of these patients waiting for transplant and the effectiveness of this therapy. MATERIALS AND METHODS: Since 1991, eight patients affected by amyloidosis have been evaluated and enrolled on the waiting list for transplant: five affected by AL lambda type; two by APO A1; and one by TTR. Four were transplanted, three died waiting for a donor (two from cardiac failure, one from sudden death), and one has been recently transplanted after 17 months on waiting list. RESULTS: Since 1985, 713 patients underwent heart transplantation in our center, five of whom were affected by amyloidosis (0.7%). Two are still alive (60 and 41 months) without evidence of cardiac amyloidotic infiltration. One patient recently underwent a combined heart-liver transplantation. Two patients died after the intervention: one sudden death after 23 months with amyloidotic infiltration of transplanted heart, and one multiple organ failure (MOF) due to progression of the systemic disease. CONCLUSIONS: Despite the small size of the group preventing us from drawing definitive conclusion, heart transplantation may prevent therapy to arrest organ damage in patients with isolated cardiac involvement. Cardiac events are the main cause of death. Patients must be followed-up for evolution of systemic disease. The midterm survival is encouraging.