Low Serum C3 Research Articles

An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema

Reduced levels of serum C4 have been considered a ubiquitous finding in hereditary angio-oedema (HAE), and consequently low C4 is often used to 'request manage' access to C1 inhibitor assays in the United Kingdom. However, in our experience normal C4 may occasionally be compatible with HAE. We audited the results of serum C4, C1 inhibitor antigen (C1inhA) and C1 inhibitor function (C1inhF) in 49 HAE patients, compared to a control group of 58 unaffected subjects. The sensitivity of low serum C4 for HAE among untreated patients was 81%; levels of complement C4 were within the normal range on nine separate occasions in five untreated HAE patients. Molecular genetic analysis of these individuals demonstrated novel mutations in the C1 inhibitor gene. The supplied reference ranges for the Quidel C1inhF enzyme-linked immunosorbent assay (ELISA) system appear to be too low, with a sensitivity of just 57% for HAE. Following optimization of the reference ranges using receiver operating characteristic analysis, low C1inhF was found to be 78% sensitive and 100% specific for HAE. The diagnosis of HAE is not excluded by normal levels of complement C4. We conclude that C1 inhibitor studies should be performed regardless of serum C4 where a high index of clinical suspicion exists.

Q fever endocarditis masquerading as Mixed cryoglobulinemia type II. A case report and review of the literature

BackgroundThe clinical manifestations of Q fever endocarditis are protean in nature. Mixed cryoglobulinemia type II is rarely a facet of the presenting clinical manifestations of Q fever endocarditis.Case presentationWe report a case of a 65-year-old pensioner with such an association and review the literature. As transesophageal echocardiograms are usually normal and blood cultures are usually negative in Q fever endocarditis, many of the manifestations (fever, rash, glomerulonephritis/evidence of renal disease, low serum C4 complement component, presence of mixed type II cryoglobulin, constitutional symptoms as arthralgias and fatigue) can be attributed to Mixed cryoglobulinemia type II per se. The use of Classic Duke Endocarditis Service criteria does not always suffice for the diagnosis of Q fever.ConclusionThe application of the modified criteria proposed by Fournier et al for the improvement of the diagnosis of Q fever endocarditis will help to reach the diagnosis earlier and thus reduce the high mortality of the disease. We would like to stress the importance of ruling out the diagnosis of Q fever endocarditis in cases of mixed type II cryoglobulinemia.

Platelet C4d is highly specific for systemic lupus erythematosus

Complement-activation product C4d is deposited on normal erythrocytes, while abnormal levels have been observed on the surface of erythrocytes of patients with systemic lupus erythematosus (SLE). This study examines whether C4d also deposits on human platelet surfaces, and whether platelet-bound C4d may provide a biomarker for SLE. We conducted a cross-sectional study of 105 patients with SLE, 115 patients with other diseases, and 100 healthy controls. Levels of C4d on the surface of platelets were examined by flow cytometry and scanning confocal microscopy. Statistical analyses were performed to determine the clinical variables associated with platelet C4d. Abnormal levels of platelet C4d were found to be highly specific for SLE. Platelet C4d was detected in 18% of patients with SLE, being 100% specific for a diagnosis of SLE compared with healthy controls and 98% specific for SLE compared with patients with other diseases (P < 0.0001). In addition, platelet C4d was significantly associated with positivity for lupus anticoagulant (P < 0.0001) and anticardiolipin antibodies of the IgG (P = 0.035) or the IgM (P = 0.016) isotype. Platelet C4d was also significantly associated with SLE disease activity according to the SLE Disease Activity Index (P = 0.039), low serum C4 (P = 0.046), an elevated erythrocyte sedimentation rate (P = 0.006), and abnormal levels of C4d on erythrocytes (P < 0.0001). This observation suggests that platelet-bound C4d may be a useful biomarker for SLE and may be a clue to the pathogenic mechanisms responsible for the myriad thrombotic and vascular complications of lupus associated with antiphospholipid antibodies.

Unusual Cause of Hypokalemic Paralysis in Aged Men: Sjögren Syndrome

Hypokalemic paralysis is a less recognized but reversible disorder in elderly patients. This report describes two elderly Chinese males (age 74 and 78 years) who had progressive muscle weakness and eventually paralysis. Physical examination showed symmetrical flaccid paralysis of extremities. Both had the major biochemical abnormality of profound hypokalemia (1.4 and 1.8 mmol/L) accompanied by high urine K+ excretion and hyperchloremic metabolic acidosis. A positive urine anion gap and alkaline urine pointed to the diagnosis of distal renal tubular acidosis. Large doses of potassium chloride supplementation were required to restore muscle strength. Pertinent investigations, including elevated titers of antinuclear antibody and rheumatoid factor, positive anti-Ro antibody, low serum C3 and C4 levels, and delayed saliva excretion on salivary scintigraphy suggested Sjögren syndrome. Despite the lack of sicca syndrome at the initial presentation, both had development of typical sicca syndrome and positive Schirmer test at the 5-month and 1-year follow-up, respectively. Potassium citrate supplement and prednisolone therapy completely corrected the hypokalemia and metabolic acidosis. Extraglandular involvement with distal renal tubular acidosis preceding the typical sicca syndrome may induce hypokalemic paralysis and unveil Sjögren syndrome in elderly males.

Mutations in Complement Factor I Predispose to Development of Atypical Hemolytic Uremic Syndrome

Mutations in the plasma complement regulator factor H (CFH) and the transmembrane complement regulator membrane co-factor protein (MCP) have been shown to predispose to atypical hemolytic uremic syndrome (HUS). Both of these proteins act as co-factors for complement factor I (IF). IF is a highly specific serine protease that cleaves the alpha-chains of C3b and C4b and thus downregulates activation of both the classical and the alternative complement pathways. This study looked for IF mutations in a panel of 76 patients with HUS. Mutations were detected in two patients, both of whom had reduced serum IF levels. A heterozygous bp change, c.463 G>A, which results in a premature stop codon (W127X), was found in one, and in the other, a heterozygous single base pair deletion in exon 7 (del 922C) was detected. Both patients had a history of recurrent HUS after transplantation. This is in accordance with the high rate of recurrence in patients with CFH mutations. Patients who are reported to have mutations in MCP, by contrast, do not have recurrence after transplantation. As with CFH- and MCP-associated HUS, there was incomplete penetrance in the family of one of the affected individuals. This study provides further evidence that atypical HUS is a disease of complement dysregulation.

C1 inhibitor deficiency: consensus document

We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio-oedema. In hereditary angio-oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non-functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification.

Angioedema hereditário: considerações sobre terapia

Hereditary Angioedema was first described by William Osler in 1888 and it is caused by a hereditary or acquired deficiency of C1 esterase inhibitor (C1-INH). Treatment is indicated for acute attacks or prophylaxis of angioedema which occur in the subcutaneous tissue respiratory or gastrointestinal tracts. Treatment includes attenuated androgens, inhibitors of kininogen or plasminogen, like tranexamic acid or e-aminocaproic acid and the administration of C1-INH concentrate. We describe the peculiarities of the treatment chosen for 10 patients (4 families) with HAE and their evolution. Ten patients (1-38 years old) with HAE were diagnosed by clinical history and laboratory evaluation. The following tests were performed for the complement system: C1-INH, C4 and C3 levels and hemolytic assay (CH50 and APH50) for the classic and alternative pathways. Treatment was initiated considering severity of symptoms, age, gender and therapeutic response of the patient. Clinical evaluation showed: 4/10 patients with recurrent subcutaneous edema; 3/10 with previous laryngeal edema and 3/10 with sporadic symptoms. Different severity of symptoms was verified in the same family. The laboratory evaluation detected: low C1-INH levels (10/10); low serum C4 level (8/10); undetectable CH50 (3/10) and low CH50 levels (6/10); low APH50 levels (2/10). Six out of ten patients did not receive any specific treatment and 2 of them had high risk of asphyxia. One adolescent had been controlled with e-aminocaproic acid, one child had been changed from danazol to tranexamic acid, a 30 year old female patient had received oxandrolone and a 38 year old man had been treated with danazol. Although HAE is caused by the same defect and affects members of the same family, various approaches have been taken to treat these patients. We observed different alternatives of prophylactic therapy for HAE, of which some did not require drug therapy.

The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children.

We reviewed the literature to analyze the risk of recurrence of hemolytic uremic syndrome (HUS) after renal transplantation in children. Among 118 children transplanted after post-diarrheal (D+) HUS, 1 (0.8%) had recurrence with graft loss. Among 63 children transplanted after HUS not associated with a prodrome of diarrhea (D-) of unknown mechanism, 13 (21%) had recurrence with graft loss. Of 11 patients with HUS associated with factor H deficiency who were transplanted, 5 lost the graft because of recurrence. Of 7 patients with HUS associated with normal factor H concentration but mutations in factor H gene who were transplanted, probably 2 had recurrence. Three patients with HUS associated with low serum C3, but no factor H deficiency or mutation lost their graft because of recurrence. The risk of recurrence in the autosomal recessive forms of HUS of unknown mechanism is not documented in children, but is around 60% in adults. A similar risk has been reported in the autosomal dominant forms. The only transplant patient with a constitutional deficiency of von Willebrand factor-cleaving protease had recurrence. Further efforts to document the post-transplant course of patients with D- HUS and progress in the understanding of the mechanisms and genetics of the disease are needed to allow more accurate prediction of the recurrence risk and to define therapeutic approaches.

The underlying diseases and follow-up in Taiwanese children screened by urinalysis.

To date, the underlying diseases and follow-up of Taiwanese children screened by urinalysis have not been reported. The grading of urine abnormalities varied from grade A (microscopic hematuria only), grade B (light proteinuria only), grade C (light proteinuria and microscopic hematuria) to grade D (heavy proteinuria). From January 1991 to August 1998, 630 students, aged 6-15 years and with positive urinary screening, were admitted to our hospital for further evaluation. Of these, 573 students had confirmed abnormal findings, 298 were boys, 275 were girls, and 294 students received a renal biopsy and have had regular follow-up visits. This study was designed to retrospectively elucidate: (1) the relationship between grading of urine abnormality and underlying disease; (2) the relationships among hypertension, grading of urine abnormality, and underlying disease; (3) the underlying disease of low serum C3 level; and (4) to determine whether urinary screening progressively decreased the number of students with end-stage renal disease (ESRD) annually. The results show that glomerular nephritis (GN) is still one of the major causes of urinary abnormalities. The most-important secondary GN was systemic lupus erythematosus (SLE) with lupus nephritis. One-quarter of the patients fulfilled at least four of the revised American Rheumatology Association (ARA) criteria for SLE at first administration, while the others who fulfilled only two to three of the revised ARA criteria had gradually developing signs and symptoms of SLE at follow-up. The percentage of SLE patients amongst anti-nuclear antibody (ANA) positive children was 72%. Membranoproliferative GN is very rare. The distribution of hypertension was 8.2% in grade A, 10.7% in grade B, 9.7% in grade C, and 28.9% in grade D urinary abnormality. There were statistical differences between grade D and either grade A or B or C (P<0.05). Lower serum C3 levels were found only in a minority of patients, including those with SLE. In this series, focal segmental glomerular sclerosis (FSGS) and active class IV lupus nephritis patients were found early enough to receive methylprednisolone pulse plus cyclosporine A therapy. To date there have been only 2 cases (5%) of FSGS with impaired renal function, and none of the lupus nephritis patients are in the predialysis stage. In conclusion, GN is still the major cause of urinary screening abnormality. ANA study is indicated in all Chinese students with abnormal urinary screening. The correlations between the severity of proteinuria and hypertension showed more-severe proteinuria in patients with nephritis as well as in those with hypertension.

Small intestinal bacterial overgrowth versus antimicrobial capacity in patients with spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis (SBP) is a serious infection in cirrhotic patients with ascites. Both defects in the host defense mechanisms and the enhancement of the offensive factor (small intestinal bacterial overgrowth (SIBO)) may contribute to the development of SBP. Therefore, the aim of this study was to evaluate the role of SIBO versus various antimicrobial capacities in the pathogenesis of SBP in cirrhotic patients. Forty-five cirrhotic patients were enrolled in this study. Bacterial overgrowth was evaluated by breath hydrogen test (BH2T). The hepatic reticuloendothelial system phagocytic index (HRESPI) was measured by intravenously injected colloid suspensions. The Child-Pugh scores in the SBP group were higher than in the non-SBP group (10.5 +/- 2.0 versus 8.0 +/- 1.8, P < 0.01). The ascitic protein concentration was significantly lower in the SBP group than in the non-SBP group (897 +/- 425 mg/l versus 1,325 +/- 453 mg/l, P < 0.01). Furthermore, the serum C3 concentration was lower in the SBP group than in the non-SBP group (43.1 +/- 13.6 ng/dl versus 73.2 +/- 26.4 ng/dl, P < 0.01). The serum C4 concentration was also lower in the SBP group than in the non-SBP group (12.4 +/- 4.0 ng/dl versus 16.9 +/- 6.6 ng/dl, P < 0.05). The incidence of SIBO was higher in the SBP group than in the non-SBP group (68.2% versus 17.4%, P < 0.01). HRESPI values were significantly higher in the two groups of cirrhotic patients than in the normal reference. However, there were no statistical differences in HRESPI between the two groups (8.4 +/- 2.8 min in the SBP group versus 7.9 +/- 2.8 min in the non-SBP group). The results of this study showed that the hepatic reticuloendothelial function is impaired in cirrhotic patients, but the degree of impairment does not differ between patients with and without previous history of SBP. Lower ascitic total protein, lower serum C3 and C4 concentrations, and presence of SIBO are all risk factors for SBP. Based on the results of our study, defects in the host defense mechanisms and the enhancement of the offensive factor (SIBO) may act in concert for the development of SBP.

Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.

Acquired deficiencies of certain complement proteins and impaired opsonisation activity have been implicated in the pathogenesis of the increased susceptibility to infections of patients with alcoholic cirrhosis. Serum concentrations of C3 and C4, plasma concentrations of C3bc, C9, and the terminal C5b-9 complement complex (TCC), and haemolytic complement activity (classic and alternative pathway) of serum, and serum opsonic activity were determined in 46 patients with compensated alcoholic cirrhosis, 31 who were decompensated, and in 15 healthy subjects. After 19 months (median) the investigated variables were analysed for their use in prognosis of recurrent infections and survival. C3 and C4 concentrations and the haemolytic complement activity of the alternative pathway were decreased in decompensated cirrhotic patients compared with controls (p < 0.01). Univariate analysis (log rank test) showed that low concentrations (< or = lower quartile) of C3 (p < 0.001) and C3bc (p < 0.05), haemolytic complement activity of the alternative pathway (p < 0.01) and classic pathway (p < 0.05), and decompensated cirrhosis (p < 0.001) were associated with an increased risk of infection and increased mortality. Multivariate (Cox) analysis showed that low C3 concentrations and decompensation of cirrhosis were significant predictors of infections and mortality (p < 0.02). Low serum C3 concentrations and decreased haemolytic complement function predisposes to infection and increased mortality in patients with alcoholic cirrhosis.

Discordant renal histopathologic findings and complement profiles in membranoproliferative glomerulonephritis type III

Patients with membranoproliferative glomerulonephritis (MPGN) type III and a low serum C3 concentration tend to have evidence for a nephritic factor of the terminal complement pathway (Nft). Complement profiles were studied in three patients with MPGN type III and low serum C3 concentrations. Serum C3 concentrations were 52, 21, and 14 mg/dL (normal range, 83 to 177 mg/dL). Serum C1q, C2, C4, properdin, and C5 concentrations were normal in all patients, whereas two had a slight decrease of C7 or C8. This pattern of complement activation resembles that seen with MPGN type II in which a nephritic factor activates the amplification loop (NFa). We conclude that in patients with MPGN type III the previously reported profile/presence of Nft is not always found, at least in the chronic stage of the disease, despite a low C3 value.

Pregnancy and its outcome in systemic lupus erythematosus.

In a multi-centre prospective study of systemic lupus erythematosus and pregnancy in France, 117 cases were identified from 1987 to 1992. We report significant morbidity and mortality for mother and fetus from an analysis of 103 cases. Pregnancy outcome was as follows: 28 full-term births, 48 premature births, 18 fetal losses (13 early and two late spontaneous abortions, three stillbirths), five therapeutic abortions and four elective abortions (for unwanted pregnancy). Four preterm neonates died. Lupus was active at pregnancy onset in 28 patients. Of 75 patients with inactive lupus at conception, 27 relapsed during pregnancy, and seven postpartum. Two patients with nephrotic syndrome treated with high-dose corticosteroids died from opportunistic infections. Fetal loss correlated with a history of proteinuria and absence of anti-SSA antibodies. Prematurity was related to a history of fetal loss, active lupus at pregnancy onset, hypertension and > or = 20 mg/day prednisone during pregnancy. Intrauterine growth retardation correlated with pregnancy of short duration, low serum C3 or C4, hypertension, and absence of SSA antibodies. Three of 22 newborns whose mothers had anti-SSA antibodies developed neonatal lupus: two with cutaneous involvement and one with complete atrioventricular block.

Unique C1 inhibitor dysfunction in a kindred without angioedema. I. A mutant C1 INH that inhibits C1-s but not C1-r.

We have described hereditary incomplete deficiency of the fourth component of complement (C4) in 10 members of a large kindred. C4 deficiency in this kindred is not linked to C4 loci in the HLA region. C4 synthesis is decreased, and C4 catabolism is normal in kindred members with low serum C4 levels. We have discovered a uniquely dysfunctional C1 inhibitor in all C4-deficient members of this kindred. C1 inhibitor dysfunction is revealed by incubating sera of affected members with EDTA, which destroys all C4 activity in these sera, but not in normal sera or sera from individuals with partial C4 deficiencies. The M(r) of C1 inhibitor purified from affected members is normal, but approximately 50% of this C1 inhibitor resists cleavage by trypsin (0.14 microM) at arg444, suggesting a substitution at this position. Moderate increases in trypsin, however, result in cleavage of the resistant molecules, which would not be expected if arg444 were the site of the mutation. All molecules in C1 inhibitor purified from affected members' plasma bind to activated C1s (C1-s), but approximately 50% of molecules in these preparations do not bind to activated C1r (C1r). These findings show that affected kindred members have a unique mutation in C1 inhibitor. The mutant C1 inhibitor does not prevent the activation of C1s by C1-r when serum Ca2+ is chelated by EDTA, but its inhibition of C1-s is normal in vivo, as shown by normal C2 levels, normal C4 catabolism, and absence of angioedema in C4-deficient members. The nature of the mutation, its selective failure to inhibit C1-r, and its relationship to decreased C4 synthesis remain to be defined.

The Hopkins Lupus Pregnancy Center: 1987-1991 update.

The course of pregnancy in patients with systemic lupus erythematosus is not known. The Hopkins Lupus Pregnancy Center has followed 64 patients (74 pregnancies) prospectively since 1987. Patients are seen monthly and clinical and pregnancy-related data collected, with particular emphasis on the occurrence of lupus flare. Flare rate during pregnancy was 1.63 per person-year, compared to 0.64-0.65 after delivery or in non-pregnant patients. Flare did not influence pregnancy outcome. Low serum C3 or C4 and high anticardiolipin antibody predicted pregnancy loss, and prednisone dose, aspirin use, diastolic second trimester blood pressure, C3 at first visit, and race predicted preterm birth. Maternal flare and preterm birth are important risks in lupus pregnancy. The latter can be predicted from maternal pregnancy data.

Persistent Low C3 Levels Associated with Meningococcal Meningitis and Membranoproliferative Glomerulonephritis

Recurrent meningococcal meningitis is usually related to terminal complement factor deficiencies (C5-C8); however it is not frequent with isolated primary C3 deficiency. Similarly, membranoproliferative glomerulonephritis has been described in association with primary C3 deficiencies and the presence of C3 nephritic factor. We present a case of an 18-year-old woman with relapsing meningococcal meningitis in whom membranoproliferative glomerulonephritis and persistent low serum C3 levels were found. A detailed immunological study was performed, but no other abnormalities in the complement components were found. C3 Nef was also negative. Moreover, the familiar complement studies showed an asymptomatic C4 deficiency in her mother and borderline C3 levels in her sister. The presence of persistent low serum C3 levels in the absence of other immunological abnormalities suggests that this is the cause of the relapsing meningococcal infections and the glomerular disease of this patient. We suggest that a complement deficiency, including isolated C3 deficiency, should be ruled out in all cases of relapsing meningitis. Further, the possibility of glomerular disease should be carefully considered in these patients.

Lack of relationship between low serum C4 concentrations and incipient retinopathy or nephropathy in diabetic children

Lack of relationship between low serum C4 concentrations and incipient retinopathy or nephropathy in diabetic children

Clinical and therapeutic studies in mesangial immunoglobulin A glomerulonephritis.

A long-term clinical and therapeutic study was performed in 47 patients with mesangial IgA glomerulonephritis. The male to female ration was 2.9:1. An episode of gross haematuria or the incidental discovery of asymptomatic microscopic haematuria with associated mild proteinuria heralded the apparent onset of renal disease. At the onset of observation 18 patients (38.2%) had high blood pressure. Other 17 patients developed hypertension during observation. Anaemia was uncommon. No essential abnormalities in serum protein and lipid patterns were found. Twenty-nine patients (61.6%) had higher levels of serum immunoglobulins--most frequently of IgA (42.5%). Twenty-two patients had low serum C3 levels (46.8%). The percentage of patients with renal failure increased from 21.2 to 36.1 during observation. Male sex, hypertension, proteinuria higher than 2 g/24 h, elevated ESR, high serum IgA levels, longer duration of the disease and older age of patients suggest an unfavourable outcome. Long-term treatment with a combination of azathioprine/acenocumarol, or indomethacin, or levamisole has no effect on the clinical manifestation and evolution.

Low serum C4 concentrations and diabetic complications

Low serum C4 concentrations and diabetic complications

Serum C4 concentration in the monitoring of systemic lupus erythematosus: requirement for C4 allotyping

We have examined the influence of genetic and other factors on the serum concentration of the fourth component of complement (C4) in four patients with systemic lupus erythematosus (SLE) studied over 3 to 8 years. Complement allotyping was performed to determine the number of C4 null genes in each patient. Two patients with C4 null genes had relatively low serum C4 concentrations with normal serum anti-DNA binding and no evidence of active disease. By contrast two patients without null alleles appeared to be consuming C4 when the serum C4 concentrations were within the conventional reference range. We therefore propose the use of appropriate reference ranges adjusted for the number of null alleles. Such adjusted reference ranges may improve the utility of serum C4 concentration in monitoring disease activity.