Disease-associated prion protein is not detectable in human systemic amyloid deposits.

Cerebral and cardiac amyloid deposits have been reported after scrapie infection in transgenic mice expressing variant prion protein (PrP(C)) lacking the glycophosphatidylinositol anchor. The amyloid fibril protein in the systemic amyloid deposits was not characterized, and there is no clinical or pathological association between prion diseases and systemic amyloidosis in humans. Nevertheless, in view of the potential clinical significance of these murine observations, we tested both human amyloidotic tissues and isolated amyloid fibrils for the presence of PrP(Sc), the prion protein conformation associated with transmissible spongiform encephalopathy (TSE). We also sequenced the complete prion protein gene, PRNP, in amyloidosis patients. No specific immunohistochemical staining for PrP(Sc) was obtained in the amyloidotic cardiac and other visceral tissues of patients with different types of systemic amyloidosis. No protease-resistant prion protein, PrP(res), was detectable by Western blotting of amyloid fibrils isolated from cardiac and other systemic amyloid deposits. Only the complete normal wild-type PRNP gene sequence was identified, including the usual distribution of codon 129 polymorphisms. These reassuringly negative results do not support the idea that there is any relationship of prions or TSE with human systemic amyloidosis, including cardiac amyloid deposition.

Organ transplantation in hereditary apolipoprotein AI amyloidosis.

Patients with hereditary apolipoprotein AI (apoAI) amyloidosis often have extensive visceral amyloid deposits, and many develop end-stage renal failure as young adults. Solid organ transplantation to replace failing organ function in systemic amyloidosis is controversial due to the multisystem and progressive nature of the disease and the risk of recurrence of amyloid in the graft. We report the outcome of solid organ transplantation, including dual transplants in 4 cases, among 10 patients with apoAI amyloidosis who were followed for a median (range) of 16 (4-28) and 9 (0.2-27) years from diagnosis of amyloidosis and transplantation, respectively. Eight of 10 patients were alive, seven with a functioning graft at censor. Two patients died, one of disseminated cytomegalovirus infection 2 months after renal transplantation and the other of multisystem failure following severe trauma more than 13 years after renal transplantation. The renal transplant of one patient failed due to recurrence of amyloid after 25 years. Amyloid disease progression was very slow and the natural history of the condition was favorably altered in both cases in which the liver was transplanted. Failing organs in hereditary apoAI amyloidosis should be replaced since graft survival is excellent and confers substantial survival benefit.

Relationship of granulocyte colony stimulating factor with other acute phase reactants in man.

The non-specific acute phase response in mice is associated with increased resistance to bacterial infection, which is critically mediated by granulocyte colony stimulating factor (G-CSF), but the behaviour of G-CSF in the human acute phase response is not known. Cardiothoracic surgery is a powerful acute phase stimulus and we show here that this procedure caused increased production of G-CSF, in addition to increases in the circulating concentrations of the proinflammatory cytokine interleukin (IL)-6 and the acute phase plasma proteins C-reactive protein (CRP) and serum amyloid A protein (SAA). Values of G-CSF correlated positively with IL-6 concentrations and circulating neutrophil counts, but not with CRP values. These results confirm that G-CSF is a physiological component of the acute phase response in humans that shares some of the same regulatory controls as IL-6, but its downstream effects are on neutrophils, not hepatic acute phase protein synthesis. Our observations are compatible with a protective role against bacterial infection for G-CSF in the human acute phase response, and support investigation of the prophylactic use of G-CSF in at-risk patients.

Preprocedural inflammatory markers do not predict restenosis after successful coronary stenting.

BACKGROUND: Levels of C-reactive protein (CRP), serum amyloid A protein (SAA), and interleukin-6 (IL-6) can predict coronary restenosis following angioplasty and stent deployment in patients with unstable angina. We investigated whether measurement of periprocedural inflammatory markers predicted the angiographic outcome at 6 months in stable angina patients undergoing coronary stenting. METHODS: We prospectively studied 182 patients; 152 patients underwent elective and successful stenting procedure for de novo lesions in native and nongrafted coronary arteries and 30 individuals in the control group underwent diagnostic angiography alone. CRP, SAA, and IL-6 were determined by high-sensitivity immunoassays. RESULTS: At 6 months, quantitative computer-assisted angiographic analysis in 133 patients with stents showed a binary restenosis rate of 33.8%. Statins were being taken by 80% of the patients. There were no significant differences between the pre- or postprocedure values of CRP, SAA, or IL-6 in patients with or without in-stent restenosis. CONCLUSIONS: Preprocedural inflammatory markers in stable angina subjects undergoing coronary artery stent deployment did not correlate with the development of in-stent restenosis. Differences in pathobiology between stable and unstable coronary syndromes, the widespread use of statins with anti-inflammatory activity in our cohort of patients, along with different mechanisms underlying the early angiographic appearances of restenosis as compared to clinical end points, most likely explain our findings.

Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis.

The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.

Unicentric Castleman's disease complicated by systemic AA amyloidosis: a curable disease.

BACKGROUND: Castleman's disease (angiofollicular lymph node hyperplasia) is a group of rare lymphoproliferative disorders sharing characteristic clinical and histological features, and usually accompanied by a marked systemic inflammatory response. All types may be complicated by acquired systemic amyloidosis, usually of AA type, but occasionally of AL type associated with monoclonal gammopathy. DESIGN: Descriptive study of five patients with unicentric Castleman's disease complicated by systemic AA amyloidosis. METHODS: A diagnosis of amyloidosis was confirmed by microscopy and immunohistochemical staining. Serum concentrations of C-reactive protein (CRP) and serum amyloid A protein (SAA) were measured by immunoassays. Radiolabelled serum amyloid P component scintigraphy was used to monitor the progress of amyloid deposition. RESULTS: In four patients the primary diagnosis was made only after years of investigation of systemic symptoms. The tumours were resected in all cases, leading to remission of the systemic inflammatory state. Long-term follow-up in four patients, including scintigraphy, showed regression of amyloid deposits. DISCUSSION: This rare but usually fatal condition can be cured surgically even in advanced cases. Awareness of the diagnosis and its correct management are important in investigation of patients with unexplained systemic symptoms, especially associated with systemic amyloidosis.

Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein.

BACKGROUND: Reactive systemic (AA, secondary) amyloidosis occurs in chronic inflammatory diseases, and most patients present with nephropathy. The amyloid fibrils are derived from the circulating acute-phase reactant serum amyloid A protein (SAA), but the relation between production of fibril precursor protein, amyloid load, and clinical outcome in AA and other types of amyloidosis is unclear. METHODS: We studied amyloidotic organ function and survival prospectively for 12-117 months in 80 patients with systemic AA amyloidosis in whom serum SAA concentration was measured monthly and visceral amyloid deposits were assessed annually by serum amyloid P component scintigraphy. Underlying inflammatory diseases were treated as vigorously as possible. FINDINGS: Amyloid deposits regressed in 25 of 42 patients whose median SAA values were within the reference range (<10 mg/L) throughout follow-up, and amyloidotic organ function stabilised or improved in 39 of these cases. Outcome varied substantially among patients whose median SAA concentration exceeded 10 mg/L, but amyloid load increased and organ function deteriorated in most of those whose SAA was persistently above 50 mg/L. Estimated survival at 10 years was 90% in patients whose median SAA was under 10 mg/L, and 40% among those whose median SAA exceeded this value (p=0.0009). INTERPRETATION: Although isolated amyloid fibrils are stable in vitro, AA amyloid deposits exist in a state of dynamic turnover, and outcome is favourable in AA amyloidosis when the SAA concentration is maintained below 10 mg/L. The potential for amyloid to regress and for the function of amyloidotic organs to recover support therapeutic strategies to decrease the supply of amyloid fibril precursor proteins in amyloidosis generally.

Pathogenesis, diagnosis and treatment of systemic amyloidosis.

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that disrupt tissue structure and cause disease. Although about 20 different unrelated proteins can form amyloid fibrils in vivo, all such fibrils share a common cross-beta core structure. Some natural wild-type proteins are inherently amyloidogenic, form fibrils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino-acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the fibrils, amyloid deposits always contain the non-fibrillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes specific calcium-dependent binding to amyloid fibrils. SAP contributes to amyloidogenesis, probably by stabilizing amyloid fibrils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, specific, non-invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid fibril precursor proteins leads to regression of amyloid deposits with clinical benefit. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end-stage organ failure by dialysis or transplantation, and vigorous efforts to control underlying conditions responsible for production of fibril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of fibrillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid fibril clearance in vivo.

Effect of alcohol consumption on systemic markers of inflammation.

BACKGROUND: Epidemiological studies suggest that light to moderate alcohol intake is associated with lower all-cause mortality than abstention or heavy alcohol intake, primarily through reduced risk of coronary heart disease. The underlying mechanisms are incompletely understood. METHODS: We investigated the association between alcohol consumption (assessed by a 7-day food record) and concentrations of C-reactive protein (CRP), alpha1-globulins, alpha2-globulins, albumin, and transferrin, and leucocyte count in a sample of 2006 men and women aged 18-88 years participating in a national health survey carried out in former West Germany in 1987-88. Analyses were based on 781 men and 995 women with complete data. FINDINGS: Among men, alcohol consumption showed a U-shaped association with mean values of CRP (p for linear term 0.65, for quadratic term 0.048), alpha1-globulins (p=0.20, 0.0006), alpha2-globulins (p=0.82, 0.31), and leucocyte count (p=0.51, 0.26) even after adjustment for age, smoking, body-mass index, HDL and LDL cholesterol, history of hypertension, education, and income. There were inverted U-shaped associations between the negative acute-phase reactants albumin (p=0.41, 0.006) and transferrin (p=0.14, 0.28) and alcohol intake. In women, the associations were less strong for CRP (p=0.35, 0.31), leucocyte count (p=0.28, 0.15), and transferrin (p=0.86, 0.83). Concentrations of alpha1-globulins and alpha2-globulins were inversely related to alcohol consumption, and albumin showed a positive association with increasing alcohol intake in women. INTERPRETATION: Non-drinkers and heavy drinkers had higher CRP concentrations than moderate drinkers. In view of the robust association between markers of inflammation, especially CRP, and risk of coronary heart disease, an anti-inflammatory action of alcohol could contribute to the link between moderate consumption and lower cardiovascular mortality.

Renal transplantation for amyloid end-stage renal failure-insights from serial serum amyloid P component scintigraphy.

Although end-stage renal failure (ESRF) is common in systemic amyloidosis, few such patients receive renal transplants. Serum amyloid P component (SAP) scintigraphy is a specific method for the imaging and quantification of amyloid deposits in vivo, which has not previously been used to evaluate the outcome of renal transplantation in patients with amyloidosis. Evidence of renal graft amyloid was sought by SAP scintigraphy in 15 patients with systemic amyloidosis who had undergone renal transplantation 42-216 months (median, 73 months) previously. Prospective serial scans were obtained annually in eight cases. Renal grafts studied shortly after transplantation gave blood-pool images. The grafts remained normal in all patients whose underlying amyloidogenic disorder had remitted, whereas there was abnormal uptake of labelled SAP, indicating graft amyloidosis, in four out of 10 patients whose amyloid fibril precursor protein supply had not diminished. Graft amyloidosis was corroborated by renal dysfunction in each case, and by histology in one patient. SAP scintigraphy enables renal transplant grafts to be monitored noninvasively for involvement by amyloid. The lack of graft amyloidosis in all patients in whom the amyloidogenic underlying disorder had remitted, and in more than half of those in whom it had not, supports the use of renal transplantation for ESRF in systemic amyloidosis.

Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses.

OBJECTIVE: To assess associations between baseline values of four different circulating markers of inflammation and future risk of coronary heart disease, potential triggers of systemic inflammation (such as persistent infection), and other markers of inflammation. DESIGN: Nested case-control comparisons in a prospective, population based cohort. SETTING: General practices in 18 towns in Britain. PARTICIPANTS: 506 men who died from coronary heart disease or had a non-fatal myocardial infarction and 1025 men who remained free of such disease until 1996 selected from 5661 men aged 40-59 years who provided blood samples in 1978-1980. MAIN OUTCOME MEASURES: Plasma concentrations of C reactive protein, serum amyloid A protein, and serum albumin and leucocyte count. Information on fatal and non-fatal coronary heart disease was obtained from medical records and death certificates. RESULTS: Compared with men in the bottom third of baseline measurements of C reactive protein, men in the top third had an odds ratio for coronary heart disease of 2.13 (95% confidence interval 1.38 to 3.28) after age, town, smoking, vascular risk factors, and indicators of socioeconomic status were adjusted for. Similar adjusted odds ratios were 1.65 (1.07 to 2.55) for serum amyloid A protein; 1.12 (0.71 to 1.77) for leucocyte count; and 0.67 (0.43 to 1.04) for albumin. No strong associations were observed of these factors with Helicobacter pylori seropositivity, Chlamydia pneumoniae IgG titres, or plasma total homocysteine concentrations. Baseline values of the acute phase reactants were significantly associated with one another (P<0.0001), although the association between low serum albumin concentration and leucocyte count was weaker (P=0.08). CONCLUSION: In the context of results from other relevant studies these findings suggest that some inflammatory processes, unrelated to the chronic infections studied here, are likely to be involved in coronary heart disease.

The protofilament substructure of amyloid fibrils.

Tissue deposition of normally soluble proteins, or their fragments, as insoluble amyloid fibrils causes the usually fatal, acquired and hereditary systemic amyloidoses and is associated with the pathology of Alzheimer's disease, type 2 diabetes and the transmissible spongiform encephalopathies. Although each type of amyloidosis is characterised by a specific amyloid fibril protein, the deposits share pathognomonic histochemical properties and the structural morphology of all amyloid fibrils is very similar. We have previously demonstrated that transthyretin amyloid fibrils contain four constituent protofilaments packed in a square array. Here, we have used cross-correlation techniques to average electron microscopy images of multiple cross-sections in order to reconstruct the sub-structure of ex vivo amyloid fibrils composed of amyloid A protein, monoclonal immunoglobulin lambda light chain, Leu60Arg variant apolipoprotein AI, and Asp67His variant lysozyme, as well as synthetic fibrils derived from a ten-residue peptide corresponding to the A-strand of transthyretin. All the fibrils had an electron-lucent core but the packing arrangement comprised five or six protofilaments rather than four. The structural similarity that defines amyloid fibres thus exists principally at the level of beta-sheet folding of the polypeptides within the protofilament, while the different types vary in the supramolecular assembly of their protofilaments.

Molecular chaperone properties of serum amyloid P component.

The selective binding of serum amyloid P component (SAP) to proteins in the pathological amyloid cross-beta fold suggests a possible chaperone role. Here we show that human SAP enhances the refolding yield of denatured lactate dehydrogenase and protects against enzyme inactivation during agitation of dilute solutions. These effects are independent of calcium ions and are not inhibited by compounds that block the amyloid recognition site on the B face of SAP, implicating the A face and/or the edges of the SAP pentamer. We discuss the possibility that the chaperone property of SAP, or its failure, may contribute to the pathogenesis of amyloidosis.

Curative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen alpha-chain variant in an English family.

A 53-year-old English woman who had been thought to have systemic monoclonal immunoglobulin light chain (AL) amyloidosis was investigated further because of her unusually long 17-year history and a suggestion of renal disease in the family. She was found to have the Glu526Val fibrinogen alpha-chain variant that causes autosomal dominant hereditary systemic amyloidosis. This has not previously been described in a British family. The mutant gene was associated with the same haplotype as in all other reported cases, suggesting a common founder. The patient had already received a renal transplant, but the graft failed within 6 years due to amyloid deposition. Progressive hepatic amyloidosis eventually caused liver failure, although the function of other organs was well preserved. She therefore received hepatic and renal transplants to replace the failed organs and the hepatic source of the amyloidogenic variant fibrinogen. Three years later she is completely well and has no amyloid deposits identifiable by serum amyloid P component scintigraphy. This is the first detailed report of hepatic transplantation for liver failure caused by amyloidosis of any type. The substantial follow-up suggests that fibrinogen alpha-chain amyloidosis is one of the inherited metabolic diseases that can be cured by liver transplantation. The mutation underlying Glu526Val fibrinogen alpha-chain amyloidosis is incompletely penetrant and has a variable phenotype that can clinically mimic AL amyloidosis. Hereditary fibrinogen amyloidosis may be more prevalent than previously suspected and, since AL amyloid is sometimes a diagnosis of exclusion, genotyping for other amyloidogenic proteins is mandatory in all cases in which the amyloid fibrils cannot be positively identified as AL.

The genetic basis of autosomal dominant familial Mediterranean fever.

Familial Mediterranean fever (FMF) is classically an autosomal recessive periodic inflammatory disease occurring in Mediterranean and Middle Eastern populations. It is caused by mutations affecting both alleles of MEFV, a gene that encodes pyrin (marenostrin), an uncharacterized neutrophil protein. Occasional reports of autosomal dominant FMF have often been discounted, on the basis that asymptomatic FMF carriers are common in certain populations, and give rise to pseudo-dominant inheritance. We performed comprehensive MEFV genotyping in five families in whom FMF appeared to be inherited dominantly. Transmission proved to be pseudo-dominant in two cases, but true dominant inheritance of FMF with variable penetrance was supported by the genotyping results in the other three families. The disease in these cases was associated with heterozygosity for either pyrin DeltaM694 alone or the compound pyrin variant E148Q/M694I, the latter occurring in two unrelated families. Complete MEFV sequencing failed to identify any coding region abnormality in the other allele in any of these cases, and, in the largest kindred, single-allele disease transmission was further supported by analysis of silent single nucleotide polymorphisms, which proved that affected individuals had at least three different complementary alleles. Studies of two further unrelated British patients with FMF associated with simple heterozygosity for pyrin DeltaM694 were also consistent with autosomal dominant inheritance. The clinical features of dominantly inherited FMF were absolutely typical, including AA amyloidosis in a patient with pyrin DeltaM694. These findings extend the spectrum of FMF, and suggest that the methionine residue at position 694 makes a crucial contribution to pyrin's function, and that a 50% complement of normal pyrin activity does not prevent susceptibility to FMF.

Enhanced inflammatory response in patients with preinfarction unstable angina.

OBJECTIVES: We assessed the extent and the time course of the acute phase response following myocardial cell necrosis and its relationship with the presence of preinfarction unstable angina (UA). BACKGROUND: Elevated levels of acute phase proteins have been reported in patients with UA and in patients with acute myocardial infarction (MI). METHODS: C-Reactive Protein (CRP), serum amyloid A protein (SAA) and interleukin-6 (IL-6) were measured in 36 patients with MI admitted within 3 h from symptoms onset. All patients had normal levels of creatine kinase and of troponin T on admission, rising above diagnostic levels within 6 to 12 h. Blood samples for CRP, SAA and IL-6 measurements were taken on admission, at 6, 24, 48, 72 h and at discharge. RESULTS: Twenty of the 36 patients studied presented an unheralded MI (Group 1); the remaining 16 patients had symptoms of unstable angina in the preceding 7 days (Group 2). Group 2 patients have much higher levels of CRP and SAA on admission (median values 8.8 vs. 3 mg/L and 28 vs. 3.4 mg/L, respectively, all p<0.001). Following the necrotic insult, despite similar infarct size and clinical signs of reperfusion, Group 2 patients had strikingly higher peaks of IL-6 (median values 85.2 vs. 19 pg/ml, p<0.05), CRP (50 vs. 31.4 mg/L, p<0.05) and SAA (228 vs. 45 mg/L, p<0.001). CONCLUSIONS: Our data demonstrated that the acute phase response is greatly enhanced in patients with preinfarction UA compared with those presenting with an unheralded MI. The significant differences in acute phase response observed in these two clinical presentations of MI indicate a major difference in their underlying pathogenetic components.

Hereditary renal amyloidosis associated with variant lysozyme in a large English family.

BACKGROUND: Two kindreds with hereditary systemic amyloidosis caused by the first two mutations to be described in the human lysozyme gene were discovered recently and study of the variant lysozyme has been powerfully informative about mechanisms of amyloid fibrillogenesis. However, the clinical manifestations in these families, additional members of which have lately been identified, have not previously been reported in detail. METHODS: The proband presented with proteinuria aged 50 and a family history of amyloidosis, and underwent renal biopsy, whole-body serum amyloid P component (SAP) scintigraphy, and sequencing of the lysozyme gene. Her family history and the phenotype of hereditary lysozyme amyloidosis were thoroughly documented and compared with the presentation and natural history of all other known patients with this condition. RESULTS: The proband belonged to an extended English family other members of which were known to have hereditary lysozyme amyloidosis. Those with amyloid in previous generations presented with renal involvement, frequently developed complications due to gastrointestinal amyloid, and died before age 60. All amyloid deposits were composed of lysozyme and complete concordance was established between amyloid and heterozygosity for a point mutation in the lysozyme gene, encoding the previously reported Asp67His substitution in the mature protein. CONCLUSION: The phenotype, reported for the first time in this extended kindred, contrasts with that of an apparently unrelated family carrying the same mutation who presented with spontaneous hepatic haemorrhage and rupture, and with the manifestations in a family with the lysozyme Ile56Thr variant who presented with dermal petechiae before proceeding to fatal visceral amyloidosis. A remarkably wide spectrum of disease can be caused by the same amyloid fibril protein, although renal involvement predominates in all cases except those dying of hepatic rupture.

Hereditary cardiac amyloidosis associated with the transthyretin Ile122 mutation in a white man.

An 83 year old white man with atrial fibrillation was admitted to hospital after a cerebral infarct. Echocardiography was characteristic of cardiac amyloid deposition and subsequent tests confirmed amyloidosis of transthyretin (TTR) type, in association with the Ile122 mutation of the TTR gene; this has only been reported previously in African Americans in whom it occurs with an allele frequency of 2%. Haplotype analysis did not suggest a different founder than for the African Ile122 mutation. Cardiac amyloidosis should be considered among elderly patients presenting with cardiac failure and/or arrhythmia, particularly if they are resistant to conventional treatment; if confirmed, it should be followed by precise characterisation of amyloid fibril type. The prevalence of autosomal dominant cardiac TTR amyloidosis in elderly white people is unknown but early diagnosis and supportive treatment may prevent complications among affected family members.

Risk factors for coronary heart disease and acute-phase proteins. A population-based study.

AIMS: Circulating levels of C-reactive protein and serum amyloid A protein increase markedly, and albumin levels fall, during the acute-phase response to tissue injury, infection and inflammation. Some acute-phase proteins have been associated with increased risks of coronary heart disease in long-term prospective studies. The aim of the present study was to determine whether circulating concentrations of C-reactive protein, albumin and serum amyloid A protein are correlated with one another, standard vascular risk factors, markers of persistent infection, or indicators of socio-economic status. METHODS AND RESULTS: We report a cross-sectional study of 704 individuals without a history of coronary heart disease from five general practices in Bedfordshire, U.K. Plasma levels of C-reactive protein and serum amyloid A protein were strongly associated with each other (2 P<0.00001) and inversely related to levels of serum albumin (2 P<0.00001). There were highly significant associations of plasma C-reactive protein concentrations with cigarette smoking and obesity (2 P<0.00001 for each). Serum albumin levels were strongly associated with blood pressure (2 P<0.0001) and plasma lipids (2 P<0.001), and concentrations of serum amyloid A protein were strongly correlated with obesity (2 P<0.0001). CONCLUSION: Previously reported long-term prospective studies have found an increased risk of coronary heart disease of about 50% in people with raised baseline levels of plasma C-reactive protein or low albumin. The strong cross-sectional associations we have found between levels of these proteins with each other and with concentrations of serum amyloid A protein suggest that some underlying process related to inflammation is likely to be of relevance to the causation of disease. Further studies are needed to determine if the strong associations of plasma levels of C-reactive protein with cigarette smoking and obesity indicate that this particular protein can mediate some of the effects of those risk factors on coronary heart disease.

Clinical, radiological and serum amyloid P component scintigraphic features of beta2-microglobulin amyloidosis associated with continuous ambulatory peritoneal dialysis.

BACKGROUND: Beta2-Microglobulin (beta2M) amyloidosis occurs in patients with end-stage renal failure (ESRF) who undergo long-term continuous ambulatory peritoneal dialysis (CAPD), but its prevalence in patients treated exclusively by CAPD is unknown. In addition, its features may differ from those of haemodialysis-associated beta2M amyloidosis because CAPD is more biocompatible. METHODS: We performed serum amyloid P component (SAP) scintigraphy, a specific technique for imaging amyloid deposits, in 13 consecutive patients with ESRF who had been dialysed for >5 years, at least 80% of the time by CAPD. Clinical and radiological features of beta2M amyloidosis were sought and compared with the results of SAP scintigraphy. RESULTS: SAP scans showed articular amyloid deposits in seven patients, all of whom had evidence of carpal tunnel syndrome and four of whom had arthralgia characteristic of dialysis amyloidosis. Typical radiographic bone cysts were present in only one case who had been dialysed for >17 years. The remaining six patients had no clinical, radiological or scintigraphic evidence of beta2M amyloidosis. CONCLUSIONS: The prevalence of beta2M amyloidosis in this study was comparable with that in reported haemodialysis populations. Many of the amyloid deposits demonstrated by SAP scintigraphy were not associated with symptoms, but larger and longer term studies are required to determine whether CAPD favourably influences their clinical expression.