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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Low serum C3 concentrations and decreased haemolytic complement function predisposes to infection and increased mortality in patients with alcoholic cirrhosis.

Anti-interleukin-6 autoantibodies in plasma are associated with an increased frequency of infections and increased mortality of patients with alcoholic cirrhosis.

Altered cytokine metabolism has been implicated in the pathogenesis of alcoholic liver disease. Recently, autoantibodies to cytokines have been proposed to act as modifiers of cytokine functions. In this study plasma levels of anti-interleukin-1 alpha (IL-1 alpha autoantibodies and anti-IL-6 autoantibodies were determined by RIAs in 96 patients with alcoholic cirrhosis and in 16 healthy individuals. After 19 months (median) the prognostic significance of the cytokine autoantibodies was investigated using univariate analysis (Log-rank test) and multivariate regression analysis (Cox model). The seroprevalences of anti-IL-1 alpha autoantibodies and anti-IL-6 autoantibodies (42 and 18%, respectively) in the patients were not different from healthy individuals and did not relate to severity of liver disease. The presence of anti-IL-1 alpha autoantibodies was of no prognostic significance. Independent of severity of liver disease, patients with anti-IL-6 autoantibodies in plasma had a higher risk of acquiring infections and higher risk of death (P < 0.02) compared to patients without anti-IL-6 autoantibodies. The authors concluded that anti-IL-6 autoantibodies are associated with increased mortality when present in the plasma of patients with alcoholic cirrhosis, which is probably secondary to recurrent infections, but not to underlying severity of liver disease.

[Plasma calprotectin. A new prognostic marker of survival in alcoholic liver cirrhosis]. / Plasmacalprotektin. En ny prognostisk markør for overlevelse ved alkoholisk levercirrose.

The purpose of this study was to determine plasma concentrations of calprotectin in patients with different severity of alcoholic cirrhosis. Additionally, the prognostic value of calprotectin for recurrent infections and for survival was investigated after a median observation period of 19 months. No difference was found in calprotectin levels when comparing healthy controls (n = 16), compensated (n = 50) and decompensated cirrhotics (n = 34). However, high calprotectin concentrations (> median) was a significant prognostic marker of poor survival (p = 0.001, Log-rank test). Calprotectin levels (> median) showed an independent and much higher prognostic value than variables of liver disease (multivariate Cox model). During follow-up calprotectin levels (> median) were also a predictor of recurrent infection (p = 0.009, Log-rank test). Thus, in patients with alcoholic cirrhosis, plasma calprotectin appears to be a new prognostic marker of survival, which seems independent of severity of liver disease. Furthermore, high plasma calprotectin levels may characterize a group of cirrhotics with recurring bacterial infections.

Serum clusterin and vitronectin in alcoholic cirrhosis.

Clusterin and vitronectin are multifunctional regulatory proteins which both serve as complement lysis inhibitors. Previous data have strongly suggested that serum vitronectin is mainly produced in the liver, whereas the biosynthetic origin for serum clusterin has not been determined. In the present study we aimed to determine the role of the liver in producing these proteins and to evaluate the proteins as possible markers of liver failure. We therefore quantified clusterin and vitronectin in serum from patients suffering from alcoholic liver cirrhosis (n = 83), and in serum-free culture supernatants from the hepatoma cell line HepG2. The median clusterin concentration was 0.20 g/l in cirrhosis and 0.37 g/l in the controls, whereas corresponding vitronectin values were 0.19 and 0.26 g/l, respectively. The concentration of both proteins showed significant correlation (p < 0.0001) with disease severity and with established plasma markers of hepatic synthetic function, such as albumin and prothrombin complex. The clusterin level, but not the vitronectin level, correlated with survival (p = 0.005). The rates of synthesis of clusterin, vitronectin and C3 from HepG2 cells were 0.02, 0.21 and 1.9 micrograms/10(6) cells/24 h, respectively. From the present data we conclude that clusterin (as vitronectin and C3) is mainly produced in the liver and may be a useful marker in the evaluation of severity of liver disease and prognosis of patients with alcoholic cirrhosis.

Plasma calprotectin: a new prognostic marker of survival in alcohol-induced cirrhosis.

Plasma levels of calprotectin were determined in 84 patients with alcohol-induced cirrhosis. Calprotectin is released from disintegrating neutrophils, and plasma levels seem to reflect activation and turnover of such cells. The purpose of the study was to investigate the degree of activation of neutrophils, which has been indicated to be increased and a cause of neutrophil exhaustion in these patients. Additionally, on follow-up after a median observation period of 559 days, we investigated the prognostic value of calprotectin for survival. No difference was found in calprotectin levels when comparing healthy controls with patients with compensated cirrhosis and those with decompensated cirrhosis. However, high calprotectin concentrations (> median) were a significant prognostic marker of poor survival (P = .001, log-rank test). Using a multivariate Cox proportional hazard model, the prognostic value of calprotectin seemed independent of severity of liver disease evaluated on eight clinical and biochemical variables of liver disease. Divided into groups by the median calprotectin concentration, analysis of survival was performed in the whole series of patients (n = 84) as well as in patients who were completely without signs of recent or actual infection (n = 54). In both groups, calprotectin levels (> median) showed a much higher prognostic value than albumin, prothrombin complex, bilirubin, and ascites. During follow-up, calprotectin levels (> median) were also a predictor of recurrent infection (P = .009). Thus, in patients with alcoholic cirrhosis, plasma calprotectin seems to be a new prognostic marker of survival, which seems independent of the severity of liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Mannan-binding protein and complement dependent opsonization in alcoholic cirrhosis.

Mannan-binding protein is synthesized by the liver and functions in first-line host defence by opsonizing mannose-rich microorganisms due to activation of the classical complement pathway independent of Clq, and by an intrinsic ability to opsonize and mediate phagocytosis. We have investigated whether the increased susceptibility to bacterial infections in patients with cirrhosis could be explained by low plasma concentrations of mannan-binding protein and impaired complement-dependent opsonization. We examined 51 patients with compensated alcoholic cirrhosis, 34 who were decompensated and 16 healthy controls. Irrespective of group, we found a significant correlation (p < 0.05) between plasma mannan-binding protein concentration and deposition of the complement opsonin C4 on mannan from baker's yeast. In contrast to what was expected, this kind of opsonization and plasma levels of mannan-binding protein were significantly increased in the patients with decompensated cirrhosis (p = 0.01 and p = 0.007, respectively). A significant correlation (0 < 0.05) was found between mannan-binding protein and erythrocyte sedimentation rate, fibrinogen and haptoglobin in these patients. Though the correlations were weak (rho = 0.49, rho = 0.48 and rho = 0.40, respectively), the elevated levels of mannan-binding protein in the patients with decompensated cirrhosis may reflect an acute phase reaction. It is concluded that plasma levels of mannan-binding protein are increased in patients with decompensated cirrhosis and that complement-dependent opsonization of mannan does not seem to be compromized in patients with alcoholic cirrhosis.

[Attitude of hospital personnel to the risk of hepatitis B and vaccination. A questionnaire study]. / Et hospitalspersonales holdning til hepatitis B-risiko og vaccination. En spørgeskemaundersøgelse.

The aim of the study was to find out why there was a low attendance at a vaccination campaign against hepatitis B carried out amongst hospital staff in Copenhagen (Bispebjerg Hospital). An anonymous questionnaire was sent to 653 employees in June 1991. Subjects were asked to describe occupational percutaneous and mucocutaneous blood exposure and vaccination status, as well as why they had not become vaccinated. Three hundred and forty-three (51%) subjects responded. Sixty percent had been exposed to blood during the last six months, especially doctors (79.6%), both physicians and surgeons, registered nurses (66.7%) and laboratory technicians (39.4%). Sixty-seven percent had started vaccination against hepatitis B and 86.7% had completed three vaccinations. Reasons not to become vaccinated were: afraid of secondary effects, doubt about the security of the vaccine, didn't receive any offer of vaccination, low risk of blood exposure and had not thought about it. In conclusion, a lot of hospital staff members have a high risk of blood exposure and thus possibility of infection with a blood-transmitted disease. Information about hepatitis B and information about the vaccine is important. All doctors, both physicians and surgeons, ought to be vaccinated against hepatitis B. Instructions against blood exposure need to be repeated over and over again.

[Preventive hepatitis B vaccination of hospital staff]. / Profylaktisk hepatitis B vaccination af et hospitalspersonale.

UNLABELLED: In March 1990, a vaccination campaign against hepatitis B was organized in a municipal hospital in Copenhagen (Bispebjerg Hospital). The hospital staff (830 subjects) at risk of infection with hepatitis B were offered vaccination with Engerix B. The vaccination was given as Engerix B (recombinant DNA vaccine) in muscle deltoid after 0, 1 and 6 months. Antibody level was measured after one month. A total of 362 (44%) received vaccination against hepatitis B and 86% of these completed the vaccination schedule and received at least three vaccinations. 95% of the vaccinated subjects were protected after three vaccinations (HBsAg more than 10 IU/l). CONCLUSION: The recombinant DNA vaccine does not differ from the plasma-derived vaccine concerning immunogenicity and adverse reactions. There was a low compliance with the vaccination campaign, especially among doctors (35%) and laboratory technicians (35%), despite central organization.

Prognosis in glomerulonephritis. III. A longitudinal analysis of changes in serum creatinine and proteinuria during the course of disease: effect of immunosuppressive treatment. Report from Copenhagen Study Group of Renal Diseases.

A total of 395 consecutive patients with biopsy-proven glomerulonephritis were followed up for 14 years. At the time of entry to the study the patients were classified as having one of nine states of kidney disease according to serum creatinine levels and proteinuria. The transitions of the patients between the nine states were analysed. The influence of 14 independent variables including treatment with cytostatic drugs and prednisolone was estimated by the Cox proportional hazard model. Treatment with immunosuppressive drugs had an influence that emerged within the first month and continued for the next 2 months. Subsequent treatment with cytostatic drugs in combination with prednisolone delayed further improvement. Treatment with prednisolone or cytostatic drugs as single therapy for up to 6 months increased the risk of improvement of the disease, and had no significant effect on deterioration. The beneficial effect of the treatment persisted after withdrawal of the immunosuppressive drugs. The analysis revealed only a slight influence of the histological character of the glomerular changes. Post-streptococcal glomerulonephritis carried an increased tendency for improvement. Arterial hypertension affected the process in several states of kidney disease. Heavy proteinuria increased the risk of increasing serum creatinine levels.

Increased cell adherence of group B streptococci from preterm infants with neonatal sepsis.

Most women with group B streptococcus cervical colonization have uncomplicated pregnancies, but about 1% experience preterm premature rupture of membranes (PROM) followed by neonatal group B streptococcal sepsis. In such cases, streptococcal adherence to and penetration of the membranes may be an important step in the pathogenesis. In the present study, chorionic epithelial cells were incubated with group B streptococci isolated from either children developing sepsis after preterm PROM (complicated pregnancies) or from uncomplicated pregnancies. Incubation periods varied. The numbers of adherent bacteria per chorionic epithelial cell were counted by microscopic examination. After 70 minutes' incubation, the number of adherent group B streptococci in complicated pregnancies was 38, compared with 14 in uncomplicated pregnancies (P less than .001). This difference in vitro might reflect the virulence of group B streptococci.

Concanavalin A crossed affinity immunoelectrophoresis and image analysis for semiquantitative evaluation of microheterogeneity profiles of human serum transferrin from alcoholics and normal individuals.

The microheterogeneity profile of human serum transferrin from normal and alcoholic subjects was investigated qualitatively and quantitatively by means of Concanavalin A crossed affinity immunoelectrophoresis and an image analysis program. Differences in amounts of nonreacting transferrin molecules were found, suggesting an increase in triantennary glycosylation of transferrin from alcoholics compared with normal individuals. The increased amount of a highly retarded fraction in crude sera from alcoholics was demonstrated to be artefactual, probably due to entrapment or coprecipitation as the fraction disappeared after repeating the analysis with immunosorbent-purified transferrin. In conclusion, affinity electrophoresis represents a simple approach for demonstration of variations in the neutral monosaccharides of glycans and can discriminate between transferrin from alcoholics and normal individuals.

[Hepatitis B prevention after occupational exposure]. / Profylakse mod hepatitis B efter erhvervsmaessig eksposition.

The course of a programme for protection from hepatitis B after occupational exposure is assessed. Passive/active prophylaxis from hepatitis B was offered to 51 persons but only 28% completed the entire regimen. The programme for vaccination of staff prior to exposure must be intensified and not only this programme but also the protective programme after exposure must include reminders to individuals who do not follow the programme.

Hepatitis B in symptomless Danish homosexual men.

Forty eight symptomless homosexual men attending a sexually transmitted disease (STD) clinic and found by screening to have hepatitis B surface antigen (HBsAg) were followed up for a median of 10 (range six to 26) months to characterise their liver disease. Initially 33/50 (66%) of the men had increased serum liver enzyme activity and 19/47 (40%) had increased serum immunoglobulin G concentrations. Liver biopsy specimens showed acute hepatitis B in 12 (39%) and chronic hepatitis B in 19 (61%) of the 31 patients who underwent liver biopsy. The course of the infection was: acute hepatitis B in 14/48 (29%), chronic persistent hepatitis B in 23/48 (48%), chronic aggressive hepatitis B in 8/48 (17%), and cirrhosis in 3/48 (6%) of the patients. Antibodies against human immunodeficiency virus (HIV) were present in 16/45 (36%) of the patients, but the presence of antibodies to HIV did not influence the course of hepatitis B in the observation period.

Cytostatic treatment of glomerular diseases. V. Treatment of glomerulonephritis with cyclophosphamide plus prednisone, azathioprine plus prednisone and cyclophosphamide as monotherapy. A comparative study. A report from a Copenhagen Study Group of Renal Diseases.

Thirty-two patients suffering from biopsy-proven glomerulonephritis with proteinuria greater than or equal to 1.2 g/24 hours and/or creatinine clearance less than 50% of normal value were treated for 6 weeks with prednisone plus cyclophosphamide (C+P), azathioprine (A+P) or cyclophosphamide as a monotherapy (C). The effect of the treatment was evaluated after 6 and 16 weeks. The results were entered consecutively in a sequential analysis. The three treatment regimes were compared mutually as well as with the results of 16 weeks' treatment with C and placebo, published previously. Six weeks' treatment with C+P or A+P was superior to C and at least as efficient as 16 weeks' C treatment. C treatment for 6 weeks was less efficient than 16 weeks' C treatment. The side-effects of the 6 weeks' A+P or C+P treatment were fewer and less serious than those reported from the long-term C treatment.

Group B streptococci in the lower urogenital tract and late abortions.

The occurrence of group B streptococci in the lower urogenital tract of 150 women with signs of abortion and 100 women with uncomplicated pregnancy was studied. Group B streptococci appeared significantly more frequently in the urine (p less than 0.001) and in the uterine cervix (p less than 0.01) of women with abortion. Delivery resulted in 85% of patients with group B streptococci in the urine and in 42% of patients with no group B streptococci (p less than 0.001). Group B streptococci were cultured from amniotic fluid from three of eight women with intact membranes and were isolated from the urine and cervix. These bacteria were antibody coated as demonstrated by an immunofluorescence technique. Group B streptococci were recovered from blood or liver in six fetuses, including two who had group B streptococci in the amniotic fluid. The study demonstrates an association between the occurrence of group B streptococci in the urine and cervix and late abortions.

The prognostic significance of bacteremia in hepatic cirrhosis.

In order to investigate whether bacteremic cirrhosis patients generally have a more serious prognosis than non-bacteremic cirrhosis patients the survival rates of 43 bacteremic and 43 matched non-bacteremic cirrhosis patients were compared. No difference in survival existed between the two groups from the time of cirrhosis diagnosis. However, the survival rate of the bacteremic patients calculated from the onset of bacteremia was significantly shorter than the survival rate of the non-bacteremic cirrhosis patients calculated from the time of random selection (p less than 0.05). Thus the bacteremic patients at the time of bacteremia were generally in a later phase of their disease than the controls at the time of selection. Therefore, bacteremia when it occurs in cirrhosis is a severe prognostic sign, not because of its influence on survival but because of its occurrence late in the course of cirrhosis.

Malignancies following long-term azathioprine treatment in chronic liver disease. A report from the Copenhagen Study Group for Liver Diseases.

One hundred and fifty-four patients with histologically verified non-alcoholic chronic liver disease were randomized to azathioprine or prednisone treatment. After a median of 91 months observation time, the cause of death was assessed retrospectively. Autopsy was performed in 82% of 71 deaths. In the azathioprine group 33% (13/39) died from malignant neoplasia, and in the prednisone group (13%) (4/32) (p = 0.08). Considering a possible fatal outcome as a consequence of treatment, this finding urges caution in the long-term application of azathioprine at the usual dose level.

The influence of hepatic insufficiency due to alcoholic cirrhosis on the erythrocyte transketolase activity (ETKA).

The erythrocyte transketolase activity (ETKA), the stimulated erythrocyte transketolase activity (ETKAS), and the thiaminepyrophosphate effect (TPPE) were measured in 21 alcoholic patients with cirrhosis and hepatic insufficiency, 13 alcoholic patients without cirrhosis and 21 non-alcoholic persons before and after oral treatment with 100 mg of thiamine daily for 2 weeks in order to investigate the influence of hepatic insufficiency on these variables. A statistically significant rise in ETKA and fall in TPPE were found in all three groups. ETKA, ETKAS and TPPE did not differ from each other in alcoholic patients with and without cirrhosis, but TPPE was significantly higher in these patients than in the non-alcoholic persons. The conclusions are that severe cirrhosis does not affect the erythrocyte transketolase apoenzyme, the ability of the tissues to convert thiamine to thiaminepyrophosphate for use in the erythrocytes or the absorption of thiamine from the gastrointestinal tract. Besides alcoholism seems to dispose to thiamine deficiency to a higher degree than cirrhosis, and the role of the liver as a thiamine store appears to be of minor importance in the development of thiamine deficiency. Finally, ETKA, ETKAS, and TPPE are considered to be usable as thiamine deficiency indicators in patients with cirrhosis as well as in patients without cirrhosis.