Reactive Amyloidosis Research Articles

Synchronous carcinomas of stomach and bladder together with AA amyloidosis (Case Report)

Although the association and causality between chronic inflammatory states and systemic AA amyloidosis have been well established, the evidence linking solid malignancies to reactive AA amyloidosis is scarce. Here, a case of diagnosed AA amyloidosis associated with synchronous carcinomas of stomach and bladder complicated with nephrotic syndrome and renal failure is reported.

Glycosaminoglycans are part of amyloid fibrils: Ultrastructural evidence in avian AA amyloid stained with cuprolinic blue and labeled with immunogold

In domestic brown layer fowl, reactive amyloidosis of internal organs, such as liver and spleen, and of the joints is a common disorder. In a variety of amyloid types including the AA-amyloid of the chicken, in addition to amyloid fibrils, proteoglycans and glycosaminoglycans (GAGs) are found on immunohistochemistry or after extraction. The aim of the present report is to study amyloid fibrils for the ultrastructural location of GAGs by cuprolinic blue staining and immunogold labeling. Rabbit antichicken AA antiserum was used for the immunogold labeling on conventionally embedded and cryoembedded liver tissue and revealed similar results. Therefore conventional blocks could be used for further analysis. Cuprolinic blue staining was performed on blocks of joint tissue in which clearly discernable rod-shaped glycoproteins were encountered in between collagen fibrils. Moreover, it appeared to stain larger deposits which might represent amyloid. Postlabeling with the immunogold method of the cuprolinic blue-stained tissue proved that cuprolinic blue positive fibrils represented AA-amyloid fibrils. Therefore, it was concluded that the GAGs which appeared to colocalize with the fibrillar microanatomy of amyloid, represent a structural part of the amyloid fibrils and that the avian amyloid fibrils may be considered as a pathological proteoglycan.

Prevalence and Pathology of Amyloid in Atherosclerotic Arteries

To the Editor: Apolipoprotein AI (AApoAI)–associated amyloidosis is characterized by the deposition of apolipoprotein AI (apoAI) and occurs as a hereditary and a nonhereditary form. Hereditary AApoAI amyloidosis is a systemic disease leading to the deposition of amyloid in various organs and tissues and is caused by germline mutations in the APOA1 gene. Nonhereditary AApoAI amyloid is far more prevalent and characterized by deposits of nonvariant protein in atherosclerotic arteries.1–3 Despite being linked to the most common cause of morbidity and mortality in Western societies, nonhereditary AApoAI amyloid has achieved only little attention.1–4 It shares several striking similarities with secondary or reactive AA amyloidosis. Nonhereditary AApoAI amyloid occurs in the background of a local chronic inflammatory reaction, it originates from an apolipoprotein that largely associates with high-density lipoproteins (HDLs), and apoAI-containing HDL is endocytosed and retroendocytosed by macrophages, which, in themselves, are able to form amyloid in vitro. Finally, AApoAI amyloidosis is characterized by the deposition of proteolytic fragments of the precursor protein, leading us to speculate that proteolysis is involved in the pathogenesis of AApoAI amyloid.1,3 The aim of this study was to gain further insights into the pathology of nonhereditary AApoAI amyloid. See cover The prevalence and spatial distribution of amyloid, macrophages, cathepsin B (CathB), cathepsin K (CathK), cathepsin L (CathL), and carboxy methyl lysine (CML) was studied using carotid artery specimens obtained from a consecutive series of all 225 patients undergoing carotid endarterectomy with polyester patch angioplasty (Table I, available online at http://atvb.ahajournals.org) during the period from 1997 to 2003. All patients were scheduled for elective therapeutic endarterectomy and gave written informed consent in the surgical procedure. Patient characteristics were retrieved from hospital records. This study was in accordance with the guidelines of the ethics committee of the University of Magdeburg. Tissue samples were …

Long-term mortality outcome in patients with reactive amyloidosis associated with rheumatoid arthritis

It is well established that amyloidosis is a serious clinical complication that can influence the prognosis of patients with rheumatoid arthritis (RA). The purpose of the study was to obtain information on the survival and the hemodialysis (HD) of patients with amyloidosis. Eighty patients (9 men and 71 women) who were diagnosed with amyloidosis by biopsy and definite or classical RA were studied retrospectively. The average duration of RA prior to the diagnosis of amyloidosis was 15.4+/-9.4 years. The average period from the diagnosis of amyloidosis to death was 67.4 months. Forty-nine patients died of the disease (32 cases with HD and 17 cases without HD). Thirty-one patients lived (7 cases with HD and 24 cases without HD). Regarding the survival of these patients, 49 (61.3%) of the 80 patients have died. Survival rate at 28 months was 75%; at 67 months, it was 50%; and at 111 months, it was down to 25%. Mortality rate was 11.9% per year. Survival rate in dialysis at 9.8 months was 75%; at 60.6 months, it dropped to 50%; and at 100.0 months, to 25%. As for patients' survival, high onset age of amyloidosis was the major determining factor for poor survival in these patients (p<0.001). Furthermore, male patients also had poor survival (p=0.07). The long-term results were very encouraging to initiate HD in patients with end-stage renal disease due to reactive amyloidosis associated with RA.

Hereditary periodic fever and reactive amyloidosis

Hereditary periodic fever syndromes (HPF) are a group of diseases characterised by recurrences of fever and inflammation separated by symptom-free intervals. Familial Mediterranean fever (FMF) is the most frequent entity within this group of disorders which further consists of hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS). In recent years the causative genes have been identified. Reactive amyloidosis is a severe complication of HPFs. This is caused by deposition of fibrils that consist of the proteolytically cleaved acutephase protein serum amyloid A (SAA). Several factors have been identified that modulate the risk for developing amyloidosis, including SAA concentrations, polymorphisms in the SAA gene and ethnic origin. Furthermore, the risk of developing amyloidosis varies widely between the different HPFs. Colchicine is the cornerstone in the management of FMF, as it reduces the severity and frequency of attacks and is also effective in preventing amyloidosis. In the other HPFs, the introduction of anticytokine-based therapies is a promising new option in treating these inflammatory conditions and they potentially can prevent amyloidosis.

Improvement of renal function and disappearance of hepatitis B virus DNA in a patient with rheumatoid arthritis and renal amyloidosis following treatment with infliximab

Reactive systemic AA amyloidosis is a severe complication of rheumatoid arthritis (RA), occurring in 2–5% of RA patients (1). Infliximab, a monoclonal antibody against tumor necrosis factor (TNF ), is successfully used in the treatment of RA (2). TNF plays a key role in inducing the synthesis of the hepatic acute-phase reactant protein serum amyloid A, the precursor of tissue AA amyloid. There have been reports of TNF blockade treatment in patients with rheumatic diseases complicated by renal AA amyloidosis (3,4). The major concern with infliximab is the possible increase of infections, and no established data have been presented on the safety of infliximab in patients with hepatitis B virus (HBV) infection. This report describes the case of a patient with RA, renal amyloidosis, and HBV-related chronic hepatitis in whom infliximab improved renal function with the disappearance of HBV replication.

Cardiovascular Magnetic Resonance in Cardiac Amyloidosis

Amyloidosis represents a diverse group of diseases characterized by the common factor of deposition of twisted β-pleated sheet fibrils (amyloid) formed as a result of the misfolding of various proteins produced in several different pathological states. The different forms of amyloidosis are classified by the composition of the amyloid fibril. AL amyloidosis (previously designated as primary amyloidosis) is derived from light-chain immunoglobulin produced by monoclonal plasma cells.1 It is the most severe and probably, at least in the United States, the most common form of amyloidosis. The accumulation of amyloid disrupts the tissue architecture and, possibly in conjunction with a toxic effect from the light chains,2 leads to severe organ damage that may involve the kidneys, heart, liver, or peripheral nerves. Familial amyloidosis is an uncommon, autosomal dominant disease with a high degree of penetrance. Most cases result from the production of an unstable variant of the serum protein transthyretin ( ATTR amyloidosis ). More than 80 point mutations have been identified for ATTR amyloidosis, which predominantly results in neurological or cardiac dysfunction or both.1,3 A particularly common mutant transthyretin resulting from the substitution of isoleucine for valine at position 122 is found in ≈4% of the African American population, with an unknown penetrance. This mutation results in a cardiomyopathy that has been suggested to be one of the most common types of cardiomyopathy in older adult African American patients.4 Senile systemic amyloidosis is the result of the deposition of wild-type transthyretin and is almost exclusively limited to the heart. This disease may be becoming more prevalent because of the increasing age of the general population. Reactive systemic amyloidosis is the result of an overproduction of a nonimmunoglobulin protein AA and is rarely associated with any cardiac involvement. See p 186 In AL amyloidosis, cardiac involvement is common …

Transcriptional Activity of Serum Amyloid A-activating Factor-1 Is Regulated by Distinct Functional Modules

Serum amyloid A-activating transcription factor-1 (SAF-1) plays a major role in regulating transcription of several inflammation-responsive genes, including SAA and matrix metalloproteinase-1, that are implicated in the pathogenesis of reactive secondary amyloidosis, atherosclerosis, and arthritis. SAF-1 is a 477-amino acid protein with six zinc fingers. Its activation during inflammatory condition by a phosphorylation event that leads to an altered structure suggested possible structural modification of this protein as a leading cause of higher activity. However, no information is available regarding structural features that might regulate its activity. Here, we have characterized its functional domains, delineating activation and repression modules, DNA binding, and nuclear localization activities. Using GAL4AD chimeras and a DNA-binding assay with proteins prepared from various deletion constructs, the core DNA-binding domain of SAF-1 is mapped between amino acids 282 and 361, which contain second, third, and fourth zinc fingers. Results from several deletion and point mutants using green fluorescent protein reporter show that SAF-1 contains two independent nuclear localization signals; one is composed of a stretch of basic amino acids, and the other is a bipartite signal located within the core DNA-binding domain. SAF-1 contains several negative and positively functioning transactivation modules clustered at the two ends of this protein. Removal of any one of the terminal negative modules renders the SAF-1 protein functionally very active. These findings suggest that the terminal repression modules act in conjunction to regulate the functional activity of this protein.

Anaemia of chronic disease in AA amyloidosis is associated with allele 2 of the interleukin-1beta-511 promoter gene and raised levels of interleukin-1beta and interleukin-18.

In amyloid A (AA) amyloidosis the receptor for advanced glycation end products is a target for the circulating amyloid precursor protein (SAA) resulting in upregulation of the proinflammatory cytokine pathway. Besides inducing hepatic SAA synthesis the interleukin-1 cytokine family is involved in the regulation of haematopoiesis. We therefore studied the relationship between the circulating levels of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18), a new member of the IL-1 complex, as well as polymorphisms within the IL-1 cluster with the occurrence of anaemia in patients with AA amyloidosis. The study included 54 adult patients with biopsy-proven reactive amyloidosis allocated into three groups on the basis of haemoglobin (Hb) level: group I included all patients with Hb < 110 g L(-1) (n = 16); group II patients (Hb > 110 g L(-1), n = 16) were selected to match group I patients with respect to sex, age, underlying disease (seropositive, erosive rheumatoid arthritis) and renal function; and group III patients (n = 38) represented all patients (unselected) with Hb > or = 110 g L(-1). Gene polymorphisms were studied by polymerase chain reaction restriction length assay and included the base exchange at position-889 of the IL-1alpha gene, the polymorphic region at position-511 and the polymorphic locus at exon 5, position +3954 of the IL-1beta gene, as well as the IL-1 receptor antagonist (IL-1Ra) exon 2 polymorphism caused by the 86-bp tandem repeats. Plasma IL-1beta, IL-1alpha, IL-18, IL-1 Ra, SAA, ferritin, soluble transferrin receptor and erythropoietin levels were studied by enzyme immunoassays. Circulating IL-beta and IL-18 were significantly raised in the anaemic patients with AA amyloidosis when compared with group II patients (matched, Hb > 110 g L(-1)) as well as group III patients (nonmatched, Hb > or = 110 g L(-1)). A significant inverse relationship was found between IL-1beta and haemoglobin levels, as well as between IL-18 and haemoglobin levels. The frequency of allele 2 (T) of the IL-1beta-511 promoter gene was significantly increased and that of allele 1 (C) decreased in anaemic amyloid patients (group I) when compared with group II and III patients. Circulating IL-1beta levels tended to be higher amongst the IL-1beta-511 allele 2 carriers than amongst the noncarriers, as well as amongst the anaemic amyloid patients filling all criteria of anaemia of chronic disease. The occurrence of anaemia in patients with AA amyloidosis is associated with allele 2 (T) of the IL-1beta-511 promoter gene and elevated levels of circulating IL-1beta and IL-18. In AA amyloidosis the raised cytokine levels may generate a vicious cycle leading to accelerated amyloidogenesis, suppression of erythropoiesis and aggravation of the underlying inflammatory disorder.

Hypothetical structure of human serum amyloid A protein

The proteins known as serum amyloid A (SAA) play major, but relatively uncharacterized, roles in the acute phase response and are important components of the innate immune system of humans and probably all vertebrates. N-terminal fragments of the inducible isoforms, SAA1 and SAA2, are the major constituents of fibrils formed during secondary or reactive amyloidosis. Little is known about the structure of SAA beyond secondary structure analyses and circular dichroism spectroscopic data indicating significant alpha helix conformation. Analysis of the primary structure of human SAA indicates probable homology to the N-terminal domain of hemocyanins of arthropods and suggests that approximately 80% of the molecule may consist of a helical bundle with the remaining portion of the C-terminus potentially disordered. This model of SAA suggests that proposed binding sites for laminin, fibronectin, and calcium are segregated to one face of the molecule and that the heparin/heparan binding site is found in the putatively disordered region of the protein. It is possible that removal of the N-terminal 76 amino acid fragment by proteolytic cleavage found generates an unstable entity that undergoes a helix to beta strand transition analogous to the fibril process of A-beta and prion peptides.

Infliximab Treatment of Familial Mediterranean Fever and Its Effect on Secondary AA Amyloidosis

We describe a patient with a long history of familial Mediterranean fever who developed proteinuria as a result of secondary AA amyloidosis. In this patient, the inflammatory process, including recurrent attacks of arthritis, abdominal pain, nephrotic syndrome secondary to amyloidosis, and high sedimentation rate, was rapidly suppressed by treatment with infliximab and there was remarkable improvement of the proteinuria.Because TNF-alpha is a proinflammatory cytokine that plays a major role in FMF and secondary amyloid, it is an appropriate target for therapy. Our case is the first case of reactive systemic amyloidosis secondary to familial Mediterranean fever, which responded favorably to infliximab.

Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis.

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohn's disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value=0.03). The E148Q variant of MEFV was present in two of the three patients with TNF receptor-associated periodic syndrome (TRAPS) complicated by amyloid in two separate multiplex TRAPS families containing 5 and 16 affected members respectively, and the single patient with Muckle-Wells syndrome who had amyloidosis was homozygous for this variant. The R92Q variant of TNFRSF1A was present in two of 61 JIA patients with amyloidosis, and none of 31 nonamyloidotic JIA patients. No HPF gene mutations were found in 130 healthy control subjects. Although allelic variants in HPFs genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects.

Generation of amyloid A protein by the cell lines from amyloid-susceptible and -resistant mice.

It has been proposed that impaired degradation is the cause of amyloid A (AA) formation in reactive amyloidosis (Ham et al., Scand J Immunol 1997; 45: 354-60). The current SDS-PAGE of the culture medium showed that the macrophage cell line from the amyloid-susceptible mouse strain (ANA1) degraded amyloid precursor protein serum amyloid A into the AA-like amyloidogenic product of approximately 8.6 kDa but went no further, whereas cells from the resistant strain (A/J10) cleared the AA-like derivates proceeding to approximately 7.7 kDa products within the incubation period. Degradation occurred in the chemically defined medium at a slower rate than in the medium with serum. This may imply that a lack of the serum components as well as impaired degradation could contribute to the development of amyloidosis.

Tumor necrosis factor alpha, its soluble receptor I, and -308 gene promoter polymorphism in patients with rheumatoid arthritis with or without amyloidosis: implications for the pathogenesis of nephropathy and anemia of chronic disease in reactive amyloidosis.

To study tumor necrosis factor alpha (TNFalpha) -308 gene promoter polymorphism and circulating levels of TNFalpha and soluble TNF receptor type I (sTNFRI) in rheumatoid arthritis (RA) patients with and without reactive amyloidosis. In a retrospective study, we examined 55 RA patients with biopsy-proven reactive amyloidosis and 55 control RA patients without amyloidosis (matched for age, sex, rheumatoid factor titer, and RA duration). Inflammatory activity was assessed by measuring the erythrocyte sedimentation rate and C-reactive protein level. TNFalpha gene promoter polymorphism was studied using polymerase chain reaction-restriction fragment length polymorphism assay. Cytokine and receptor levels were measured by enzyme-linked immunoassays. Patients with RA and amyloidosis had significantly higher TNFalpha and sTNFRI levels than did the control RA patients. The increased circulating levels of TNFalpha correlated with interleukin-18 levels, but not with the serum amyloid A protein levels or with TNFalpha -308 gene promoter polymorphism (reported to be associated with high TNFalpha levels and certain disease susceptibilities). In the patients with RA and amyloidosis, those with anemia had significantly higher TNFalpha and sTNFRI levels than did those without anemia, and circulating TNFalpha and sTNFRI levels correlated negatively with hemoglobin concentrations. In the patients with RA and amyloidosis, those with nephropathy had significantly higher TNFalpha and sTNFRI levels than did those without nephropathy; in patients with isolated proteinuria (but no creatinine elevation) the TNFalpha level was also significantly increased, indicating that the TNFalpha elevation was not merely a consequence of impaired renal function. This study shows that circulating levels of TNFalpha and sTNFRI are significantly increased in RA patients with amyloidosis as compared with control RA patients without amyloidosis and that the increased levels may be implicated in the pathogenesis of certain disease manifestations, including anemia of chronic disease and renal pathology in reactive amyloidosis.

A case of multicentric Castleman's disease associated with advanced systemic amyloidosis treated with chemotherapy and anti-CD20 monoclonal antibody

Multicentric Castleman's disease (MCD) is a rare systemic lymphoproliferative disorder with too few patient series reported in the literature to have a clear idea about the etiology, outcome and the best treatment available. Systemic reactive amyloidosis is a very rare complication of MCD and its presence worsens the prognosis. We report a case of a 28-year-old patient with plasma-cell type, human immunodeficiency virus (HIV)-negative and human herpesvirus-8 (HHV-8)-negative MCD who responded to treatment with chemotherapy and the anti-CD20 monoclonal antibody, rituximab. Anti-CD20 therapy could be an interesting adjunctive treatment in MCD.

End-stage renal disease in familial amyloidosis ATTR Val30Met: a definitive indication to combined liver-kidney transplantation

AUTOSOMAL dominant amyloidoses characterized so far are most commonly associated with transthyretin (TTR), a plasma protein synthesized by the liver. The single gene for TTR is located on human chromosome 18; more than 70 TTR mutations have been documented. The most common type of hereditary amyloidosis is familial amyloid polyneuropathy type I (FAP, Portuguese type), a neuropathic form associated with a substitution of methionine for valine at position 30 of the TTR gene, TTR Val30Met. The largest number of patients and families with this mutation has been identified in Portugal, but now it has been recognized worldwide. FAP in Portugal usually begins in the third or fourth decade of life with death occuring about 11 years later. The clinical disease usually starts as a sensory neuropathy in the lower extremities, but autonomic and gastrointestinal features may occur early. Motor neuropathy usually manifests itself later with cardiac conduction disturbances frequently leading to the need for artificial pacing. Vitreous deposits of amyloid have been reported, most particularly in Swedish families. Cachexia has been described as a significant factor in mortality. Orthotopic liver transplantation (OLT) is widely recommended for patients affected by FAP; it is recognized as the only specific treatment for this disease. Virtually all TTR is produced by the liver, and, therefore, OLT halts the supply of variant amyloidogenic TTR (ATTR). Amyloid proteins have different organ specificity, leading to variations in clinical features. Classically, nephropathic and nonneuropathic autosomal dominant amyloidoses are associated with apolipoprotein A-I and A-II, fibrinogen A -chain, and lysozyme. Renal amyloidosis also has been described in FAP. In Portugal, approximately one third of FAP patients have clinical renal features with varying degrees of proteinuria and renal failure. The progression to end-stage renal disease (ESRD) occurs in 10% of Portuguese patients, more than 10 years after the onset of symptoms (Lobato et al, unpublished data). Although dialysis may prolong life, it does not prevent the progression of systemic amyloid involvement; death occurred, on average, at 22 months after renal replacement therapy. The cause was infection in one half of the patients (Lobato et al, unpublished data). The first successful renal transplantation in a patient with renal amyloidosis was reported in 1968, but until now this treatment has been associated with poor graft and patient survival. Most published series concerning renal transplantation in amyloidosis deal with familial Mediterranean fever or other forms of reactive amyloidosis (AA type). The results of kidney transplantation in ATTR have not been described. In patients with FAP undergoing dialysis, the potential advantages of simultaneous liver-kidney transplantation instead of isolated kidney transplantation are to avoid the progression of systemic manifestations and the recurrence of renal amyloidosis. The obstacles to renal transplantation

Facial flushing and localized Castleman's disease: an extension of the POEMS syndrome phenotype – reply

Dear Sir, We thank Dr Ma et al. for their comments concerning our article [1]. Castleman's disease is known as angiofollicular lymph node hyperplasia, which is separated into localized type and multicentric type. Multicentric Castleman's disease (MCD) presents with systemic symptoms and multiple lymphadenopathy. Clinical findings in patients with MCD are fatigue, fever, loss of weight, night sweats, anorexia and oedema; laboratory findings of MCD are anaemia, elevated ESR, hypergammagloblinaemia, and hypoalbuminaemia [2]. Some of these findings are consistent with POEMS syndrome, and the lymph node of the patients with POEMS syndrome shows Castleman's disease in about 60%[3]. Therefore, POEMS syndrome might be associated with Castleman's disease. The causes of reactive amy loidosis inc1ude chronic inflammatory disorders (e.g. rheumatoid arthritis), chronic infections and malignancy [4]. Ordi J et al. reported and reviewed amyloidosis associated with Castleman's disease; six of eight patients with amyloidosis are reactive amyloidosis [5]. Castleman's disease is classified histologically as hyaline-vascular type, plasma cell type and mixed type. In the hyaline-vascular type, the germinal centres are surrounded by multiple concentric layers of lymphocytes, which are penetrated radial capillaries surrounded by hyaline material. In the plasma-cell type, the interfollicular areas are occupied by extensive sheets of plasma cells [6]. Although the plasma cells in hilar and mesenteric lymph nodes were observed [4], there was neither swelling in the nodes nor histopathological features consistent with Castleman's disease at autopsy in our case. Castleman's disease might not be responsible for the reactive amyloidosis in our case. Received 7 November 2002; accepted 11 November 2002. Dr Y. Kihara, Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu, Japan. (fax: +81 93 692 0107: e-mail: [email protected]).

Spontaneous pneumoperitoneum: an unusual complication of systemic reactive AA amyloidosis secondary to rheumatoid arthritis

We report a 71-year-old man with reactive AA amyloidosis secondaty to rheumatoid arthritis who developed spontaneous pneumoperitoneum with intestinal pseudo-obstruction as an initial symptom. Severe deposition of amyloid in the intestinal wall was considered to play an important role in the pathogenesis of this unusual symptom. The patient has been successfully treated with total parenteral alimentation and intermediate-dose prednisolone (30mg/day). Although pneumoperitoneum usually suggests gastrointestinal perforation requiring emergency surgery, conservative therapy should be seriously considered in amyloidosis-related cases with no associated peritonitis, since multiple vital organs are probably involved by severe amyloid deposition, thus increasing the risks of surgery.

An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians

Serum amyloid A1 (SAAI), one of the two isotypes of acute phase SAA, is the predominant precursor to amyloid A (AA) protein, the chief constituent of fibrillar deposits in reactive (AA) amyloidosis. Prolonged hyperexpression of SAA protein accompanying chronic inflammation is critical to, but seems not to be sufficient for, the development of AA amyloidosis. Several previous studies have investigated the possibility of linkage between SAAI exon 3 polymorphisms and susceptibility to amyloidosis. While the SAAI. I allele was found to have a negative association with amylodosis in Japanese subjects, it showed a positive association in Caucasians. Moriguchi and colleagues recently showed that a single nucleotide polymorphism (SNP) at position -13 in the SAAl S' flanking region was more strongly associated with amyloidosis than was the exon 3 polymorphism. To test whether this SNP may be an amyloidogenic factor common to Japanese and Caucasians, we have analyzed the SAA l gene in amyloid and non-amyloid patients of both ethnic groups for the presence of T or C at position -13 and for exon 3 polymorphisms (SAAI. I, 1.3 or 1.5). The frequency of the -13T allele was 0.708 and 0.521 in Japanese rheumatoid arthritis patients with and patients without AA amyloidosis, respectively, and 0.536 and 0.196 in American Caucasian patients with AA amyloidosis and control subjects, respectively. In Caucasians, the -I3Tallele had a stronger association with amyloidosis than did the SAAI.I allele. These findings suggest that -13T is a genetic background for AA amyloidosis in both Japanese and Caucasians and the difference in prevalence of AA amyloidosis in the two ethnic groups may be due, at least in part, to a difference in the frequency of the -13T SAAI allele.

Abdominal fat aspiration biopsy and genotyping of serum amyloid A contribute to early diagnosis of reactive AA amyloidosis secondary to rheumatoid arthritis.

To detect amyloid deposits in the early phase of illness, we investigated the usefulness of abdominal fat aspiration biopsy along with genotyping of serum amyloid A (SAA) in patients with rheumatoid arthritis (RA). We performed abdominal fat aspiration biopsy with phenol Congo red staining and determined inflammatory markers, including CRP and SAA, in 217 patients with an RA history longer than 5 years (mean age, 64.1 +/- 10.6 years). Genotypes of SAA1 and 2 were investigated in 127 patients with RA by a polymerase chain reaction-restriction fragment length polymorphism analysis. In the abdominal fat aspiration biopsy 17 patients (7.8%) demonstrated amyloid deposits, which were confirmed as AA type by immunostaining on biopsied tissues from other organs, and nine of them showed no clinical symptoms ascribable to amyloidosis. RA patients with amyloidosis showed significantly higher serum levels of CRP (p < 0.05) and SAA (p < 0.0001) than those without amyloidosis. In the genotyping, amyloid deposition was significantly correlated with the frequency of SAA1.3 (p < 0.005 vs. 1.1, p < 0.05 vs. 1.5). Comparison of inflammatory markers between the number of SAA1.3 alleles showed that the SAA/CRP ratio and SAA concentration were higher in the 1.3 homozygote than in the others (p < 0.05). Two patients demonstrated amyloid deposits at the second abdominal fat biopsy one year after the first, and their SAA1 genotypes were 1.3/1.5 and 1.3/1.3. In RA patients confirmed as having SAA1.3, serial examinations with abdominal fat aspiration biopsy might contribute greatly to the early detection of amyloidosis during the long-term follow-up.