Clinical Investigator
Clin Investig (1992) 70:579-584
OriginaJ Article
© Springer-Verlag 1992
Cause and frequency of posttransfusion hepatitis after open-heart surgery H.-J. Schlayer 1, T. Peters 1, S. Preisler ~, H. Berthold 2, W. Gerok ~, and J. Rasenack 1 1 Medizinische Klinik und 2 Hygieneinstitut, Albert-Ludwigs-Universit/it, Freiburg
Summary. A total of 1476 patients who underwent open-heart surgery between 1986 and 1988 participated in a prospective study examining posttransfusion hepatitis. They received a total of 8327 units of whole blood, packed erythrocytes, or fresh frozen plasma. The aminotransferase activities were measured preoperatively and 1, 2, 3, 4, 6, 9, 12, and 24 weeks after the operation. Thirty-four patients in all (2.3 % of the transfused patients) developed posttransfusion hepatitis, which could be identified as hepatitis B in I patient and hepatitis C in 14 patients. No cause for posttransfusion hepatitis could be found in 19 cases (hepatitis of unknown origin). Hepatitis C became chronic in 5 patients. In contrast to hepatitis C, the 19 patients with hepatitis of u n k n o w n origin all showed a milder clinical course with lower maximal aminotransferase activities and a shorter duration of the hepatitis. A chronic course was not observed among them. The cause of hepatitis of unknown origin is discussed.
sion hepatitis cases could not be attributed to any of the known agents [2, 12]. On the basis of epidemiological studies, it was assumed that parenterally transmissible hepatitis non-A non-B could be caused by various infectious viruses [5, 13]. Houghton and his colleagues succeeded in cloning, sequencing, and expressing in vitro of the hepatitis C virus RNA. This enabled the design of an enzyme immune assay which can specifically detect antibodies directed against the hepatitis C virus [6, 15]. The present study was designed to determine the frequency of posttransfusion hepatitis after open-heart surgery at two German cardiosurgical centres. The influence of age, sex, type of operation, and amount of transfused blood units on the frequency of posttransfusion hepatitis was tested. Furthermore, the course as well as the causes of posttransfusion hepatitis were examined.
Posttransfusion hepatitis - Hepatitis B - Hepatitis C - Frequency - Surgery
Methods
Key words:
Posttransfusion hepatitis is still one of the most frequently encountered postoperative complications. Rates of occurence after open-heart surgery of 2% to over 10% have been reported in the literature [2, 3, 7-9, 19]. Until the beginning of the 1970s, the hepatitis B virus infection was the most frequent cause of posttransfusion hepatitis. After the discovery of the hepatitis B virus and the development and use of immunological tests, hepatitis B accounted for only about 10% of posttransfusion hepatitis. The remaining 90% of posttransfuAbbreviations: Hep of UO=hepatitis of unknown origin; ELISA=enzyrne-linked immunosorbent assay; A L A T = a l a nine aminotransferase; ASAT = asparagine aminotransferase; AT=aminotransferase; AT-A=aminotransferase activity; CMV = cytomegalovirus; EBV = Epstein-Barr virus
The 4400 patients of the cardiosurgical centers at Freiburg and Bad Krozingen were approached in the study. Some 90% of the patients agreed to participate; of these 60% received blood transfusions during or immediately after the operation (packed erythrocytes, fresh frozen plasma, or whole blood). Only 63 % of the patients who collaborated proved reliable, so that in all 1476 patients could be analysed. Blood samples were collected preoperatively and 1, 2, 3, 4, 6, 9, 12, and 24 weeks after the operation. Preoperative sera and sera taken 4, 6, 9, 12, and 24 weeks after the operation were tested for aminotransferase activities and bilirubin. The patients were divided into 3 groups based upon their postoperative values. Those with maximum aminotransferase values of 50 U/1 or more were designated as "strongly elevated" ( > 2.5 times the upper limit of normal, group A); patients with maxim u m values between 25 and 49 U/1 (1.25-2.5 times
580 Table 1. Units of blood transfused, number of patients, and average number of units per patient related to postoperative aminotransferase activities
Number of blood units Patients Units per patient
Group A
Group B
Group C
Total
366 (5%) 42 (3%) 8.7
620 (7%) 124 (8%) 5.0
7341 (88%) 1310 (89%) 5.6
8327 (100%) 1476 (100%) 5.6
Group A = strongly elevated aminotransferase activity levels (maximum value > = 50 U/I). Group B = moderately elevated aminotransferase activity levels (maximum value between 25 U/ 1and 49 U/l). Group C = slightly elevated or nonelevated aminotransferase activity levels (maximum value < = 24 U/l). The figures in brackets indicate the distribution into the different groups expressed in percentage
the upper limit of normal, group B) were "moderately elevated"; and patients with maximum values of 24 U/1 or less ( = 15
0 (0%) 1 (1%) 1 (1%) 6 (4%) 9 (6%) 4 (3%) 3 (2%) 4 (3%) 4 (4%) 0 (0%) 0 (0%) 3 (8%) 2 (9%) 0 (0%) 1 (8%) 4 (8%)
Total
42
Group B
Group C
4 (8%) 11 (9%) 19 (11%) 16 (10%) 35 (10%) 18 (11%) 10 (6%) 8 (6%) 7 (6%) 2 (3%) 2 (6%) 4 (11%) I (4%) 2 (22%) 1 (8%) 4 (8%)
Total
48 (92%) 114 (90%) 153 (88%) 142 (86%) 130 (84%) 136 (86%) 153 (92%) 125 (91%) 104 (90%) 60 (97%) 34 (94%) 29 (81%) 20 (87%) 7 (78%) 10 (84%) 45 (84%)
124
52 (100%) 326 (100%) 173 (100%) 164 (100%) 154 (100%) 158 (100%) 166 (100%) 137 (100%) 115 (100%) 62 (100%) 36 (100%) 36 (100%) 23 (100%) 9 (100%) 12 (100%) 53 (100%)
1310
1476
Table 3. Influence of the type of operation (bypass operation or valve replacement) on the postoperative aminotransferase activities Type of operation
Group A
Bypass Valve"
30 (3%) 12 (4%)
Total
42
Group B 88 (8%) 36 (11%) 124
Group C
Total
1023 (89%) 287 (85%)
1141 (100%) 335 (100%)
1310
1476
" No significant difference compared with bypass operations (Z2 test)
Table 4. Influence of the patients' age on postoperative aminotransferase activities Age (years)
Group A
< 59 > =59 a
19 (3%) 23 (3%)
Total
42
Group B
Group C
73 (10%) 51 (7%)
Total
659 (87%) 651 (90%)
124
751 (100%) 725 (100%)
1310
1476
a No significance difference compared with younger age (Xz test)
Table 5. Influence of the patients' sex on postoperative aminotransferase activities Sex
Group A
Male Female"
31 (3%) 11 (5%)
Total
42
Group B 98 (8%) 26 (10%) 124
Group C
Total
1084 (89%) 226 (85%)
1213 (100%) 263 (100%)
1310
1476
" No significant difference compared with male sex (22 test)
and patients with hepatitis of unknown origin received 7.2_+5.6 blood units. The difference was statistically insignificant. The severity and length of posttransfusion hepatitis are summarized in Table 7. Ten of 14 patients
with newly acquired hepatitis C showed peak aminotransferase activity levels of more than 100 U/1 during the 6-month observation period. Ten of 14 patients with newly acquired hepatitis C revealed aminotransferase activities elevated
582 Table 6. Causes of strongly elevated aminotransferase (AT) activity levels in group A
Table 8. Cause of moderately elevated aminotransferase activity
New infection, hepatitis B New infection, hepatitis C Preexisting hepatitis C Ethanol Preoperative elevation of AT activity Unidentified cause
1 14 4 1 3 19
Preexisting hepatitis B New infection, hepatitis C Preexisting hepatitis C Unidentified cause
1 4 4 115
Total
124
Total
42
Table 7. Severity and length of posttransfusion hepatitis.
Above,
peak aminotransferase activity (AT-A) levels related to the dignosis of hepatitis B, hepatitis C, and hepatitis of unknown origin (Hep of UO). Middle, duration of aminotransferase activity elevation related to the diagnosis of hepatitis B, hepatitis C, and hepatitis of unknown origin. Patients with aminotransferase activity levels greater or equal to 50 U/1 at two or more postoperative controls were designated as "several AT-A > = 50 U/1." Patients with an aminotransferase activity level greater or equal to 50 U/1 at a single postoperative control were designated as "single AT-A > = 50 U/1." Below, number of patients with an aminotransferase activity (AT-A) level of more than 20 U/1 2 years after the operation related to the diagnosis of hepatitis B, hepatitis C, and hepatitis of unknown origin Hep B
Hep C
Hep of UO
Peak AT-A > 100 U/1 Peak AT-A < = 100 U/1 Sum
1 0 1
10 4 14
1 18 19
Several AT-A > = 50 U/1 Single AT-A > = 50 U/1 Sum
0 1 1
10 4 14
1 18 19
AT-A2 y.aft.op. > 20 U/1 AT-A 2 y..ft.op. < = 20 U/1 Sum
0 1 1
5 7 12"
0 19 19
" Two patients had died
more than 2.5 times the upper limit of normal over several postoperative controls. In 5 of 14 patients with newly acquired hepatitis C, pathological aminotransferase activity levels were still found 2 years after the operation. In contrast, the patients with hepatitis of u n k n o w n origin showed a more favourable course: Only 1 of 19 patients reached maximum aminotransferase activity levels of more than 100 U/l, 1 of 19 patients had an aminotransferase activity elevated more than 2.5 times over the upper limit of normal several times, and 2 years after the operation all patients exhibited normalized liver enzyme activities. The cause of the moderately elevated aminotransferase activity levels of the patients in group B are summarized in Table 8. Four patients were newly infected with the hepatitis C virus. Preexistent hepatitis C infection could be diagnosed in
levels in group B
4 patients, and preexisting hepatitis B was found in 1 patient. In 115 patients, the cause of the moderately elevated aminotransferase activity levels is unknown. Discussion
The present study examines the cause and frequency of acute posttransfusion hepatitis. The aminotransferase activities (asparagine and alanine, ASAT and ALAT) were measured between the 4th and the 24th weeks postoperatively in 1476 patients, who had received a total of 8327 units of blood during or immediately after open heart surgery. Forty-two patients showed aminotransferase activities elevated more than 2.5 times the upper limit of normal (group A). After subtracting patients with preexisting liver disease (preexisting hepatitis C, ethanol consumption, preexisting liver disease of u n k n o w n cause), posttransfusion hepatitis was indicated for 34 patients from group A. If one adds the 4 patients with newly contracted hepatitis C from group B, the number of patients with posttransfusion hepatitis rises to 38. Therefore, the frequency of posttransfusion hepatitis is 2.6%. This value is comparable with findings from England [7], The Netherlands [19], France [3], and Australia [9]. The frequency of posttransfusion hepatitis in the countries above is considerably lower than in the U S A [2] and Italy [8], where frequencies of 10% were reached. As expected, the age and sex of the patient and the type of operation (valve or bypass) had no influence on membership in group A. There tended to be a relationship between the number of blood transfusions and membership of group A, but the Wilcoxon rank sum test proved not significant at a limit of 5%. This could be explained by an unknown stratification (e.g., infection by a donor with a rare blood group). In the literature, the portion of hepatitis C in chronic posttransfusion hepatitis is stated as between 59% and 84% [10, 14-16, 18]. On the other hand, the portion of hepatitis C in acute resolving posttransfusion hepatitis is reported at between 15% and 25% [15, 18]. The present examination
583 included all patients with acute and chronic posttransfusion hepatitis w i t h o u t consideration o f the further course. I f the 4 patients with newly contracted hepatitis C f r o m g r o u p B are added to the 14 patients f r o m g r o u p A, the p o r t i o n o f hepatitis C in p o s t t r a n s f u s i o n hepatitis a m o u n t s to 4 7 % (18 o f 38 patients). Raised levels o f aminotransferase activities 2 years after the operation, reflecting the developm e n t o f chronic hepatitis, were observed in 5 o f 38 patients with posttransfusion hepatitis. All these patients had a n t i - H C V antibodies, so that the portion o f hepatitis C in chronic posttransfusion hepatitis rises to up to 100%. Thus, the present examination agrees with the literature. The clinical course o f hepatitis C is characterized by a frequent transition to chronic hepatitis. In the present study, 5 o f 18 patients who contracted hepatitis C became chronic, c o r r e s p o n d i n g to 28%, However, the actual figure might be higher for two reasons: (1) Sera o f two patients who had died were not available 2 years after the operation. (2) F l u c t u a t i o n s o f the aminotransferase activity levels; up to tenfold variations within a few days have been r e p o r t e d for hepatitis C [21]. In c o n t r a s t to hepatitis C, the 19 patients with hepatitis o f u n k n o w n origin showed a milder clinical course. This can be deduced f r o m the lower m a x i m u m aminotransferase activity levels and the shorter d u r a t i o n o f the hepatitis. A chronic course was not observed. Several causes o f hepatitis o f u n k n o w n origin are conceivable: In I patient, posttransfusion hepatitis caused by the hepatitis B virus was detected. M u t a n t s o f the hepatitis B virus with a very low antigenic concentration in the serum or m u t a n t s with changes o f their antigenic structure m a y escape traditional immunological detection. P r o o f o f H B V - D N A in the serum o f patients with H B s A g negative chronic hepatitis has been described in the literature [20]. It is also conceivable that m u t a n t s o f the hepatitis C virus which c a n n o t be detected by the present tests are responsible for hepatitis o f u n k n o w n origin. This seems possible as the antigens o f the hepatitis C virus have not yet been sufficiently characterized and since R N A viruses tend to high mutation rates. - In the older literature, two different N A N B viruses with different biochemical properties and inc u b a t i o n times have been described [1, 4, 11, 17]. A n a n t i - H C V seroconversion only occurs for 1 5 % - 2 5 % o f acute, healing posttransfusion hepatitis [15, 20]. Thus, the acute, healing posttransfusion hepatitis could also be caused by a different virus, n o t yet identified. -
-
Acknowledgements. We wish to thank the staff of the Chirurgische Universit/itsklinik, Abteilung ffir Herz- und Gef~gchirurgie, Albert-Ludwigs-Universit/it, Freiburg, and the staff of the Benedikt Kreutz Rehabilitationszentrum, Bad Krozingen, for their help and assistance during the study period and J. Fehr, M. Falasca, and H. Bexter for their technical assistance.
R e f e r e n c e s
1. Aach RD, Lander JJ!: Shermann LA (1978) Transfusion transmitted viruses: interim analysis of hepatitis among transfused and nontransfused patients. In: Vyas GN, Cphen SH, Schmid R (eds) Viral hepatitis, a contemporary assessment of etiology, epidemiotogy, pathogenesis and prevention. Franklin Institute Press, Philadelphia, pp 383-396 2. Alter HJ, Purcell RH, Holland PV, Feinstone SM, Morrow AG, Moritsugu Y (1975) Clinical and serological analysis of transfusion-associated hepatitis. Lancet II: 838-841 3. Aymard JP, Janot C, Gayet S, Guillemin C, Canton P, Gaucher P, Streiff F (1986) Post-transfusion non-A, non-B hepatitis after cardiac surgery. Vox Sang 51:236-238 4. Bradley DW, Maynard JE, Popper H, Cook EH, Ebert JE, McCaustland KA, Schable CA, Fields HA (1983) Posttransfusion non-A, non-B hepatitis: physicochemical properties of two distinct agents. J Infect Dis 148:254-265 5. Bradley DW, McCaustland KA, Cook EH, Schable CA, Ebert JW, Maynard JE (1985) Posttransfusion non-A, nonB hepatitis in chimpanzees. Physiochemical evidence that the tubule-forming agent is a small, enveloped virus. Gastroenterology 88 : 773-779 6. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:35%362 7. Collins JD, Bassendine MF, Codd AA, Collins A, Ferner RE, James OFW (1983) Prospective study of post-transfusion hepatitis after cardiac surgery in a British centre. Br Med J 287:1422-1424 8. Colombo M, Oldani S, Donato MF, Borzio M, Santese R, Roffi L, Vigano P, Cargnel A (1987) A multicenter study of posttransfusion hepatitis in Milan. Hepatology 7:709712 9. Cossart YE, Kirsch S, Ismay SL (1982) Post-transfusion hepatitis in Australia. Lancet I:208-213 10. Courouce AM, Jullien AM, Vedrenne JB, Habibi B (1990) Anti-hepatitis C antibodies in prospectively followed-up transfused patients. Vox Sang 58 : 226-227 11. Craske J, Dilling N, Stern D (1975) An outbreak of hepatitis associated with intravenous injection of factor VIII concentrate. Lancet II : 221-223 12. Feinstone SM, Kapikain AZ, Purcell RH et al. (1975) Transfusion-associated hepatitis not due to hepatitis type A or B. N Engl J Med 292:767-770 13. He LF, Alling D, Popkin T, Shapiro M, Alter HJ, Purcell RH (1987) Determining the size of non-A, non-B hepatitis virus by filtration. J Infect Dis 156:636-640 14. Hopf U, MSller B, Kfither D, Stemerowicz R, Lobeck H, Lfidtke-Handjery A, Walter E, Blum HE, Roggendorf M, Deinhardt F (1990) Long-term follow-up of posttransfusion and sporadic chronic hepatitis non-A, non-B and frequency of circulating antibodies to hepatitis C virus (HCV). J Hepatol 10 : 69-76 15. Kuo G, Choo QL, Alter H J, Gitnik GL, Redeker AG, Purceil RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Yegtmeier TE, Bonino F, Colombo M, Lee WS, Kuo C, Berger K, Shuster JR, Overby LR, Bradley DW, Houghton
584 M (1989) An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362-364 16. Mattsson L, Weiland O, Glaurnann H (1990) Application of a numerical scoring system for assessment of histological outcome in patients with chronic posttransfnsion non-A, non-B hepatitis with or without antibodies to hepatitis C. Liver 10:257-263 17. Mosey JW, Redeker AG, Feinstone SM, Purcell RH (1977) Multiple hepatitis viruses in multiple attacks of acute viral hepatitis. N Engl J Med 296:75-78 18. Poel CL van der, Reesink HW, Lelie PN, LeentvaarKuypers A, Choo QL, Kuo G (1989) Anti-hepatitis C antibodies and non-A, non-B post-transfusion hepatitis in The Netherlands. Lancet I1:297-299 19. Reesink HW, Leentvaar-Kuypers A, Poel CL van der, Lelie PN, Pietersz RNI, Mulder-Folkerts DKF, Pieters T, Ende A van den, Schaasberg W, Coutinho RA (1988) Non-A, non-B posttransfusion hepatitis in open heart surgery patients in The Netherlands : preliminary results of a prospective study. In: Zuckermann AL (ed) Viral hepatitis and liver disease. Liss, New York, pp 553-557
20. Thiers V, Fujita Y, Takahashi H, Schellekens H, Reus A de, Driss F, Degott C, Isselbacher K, Tiollais P, Wands J, Brechot C (1988) Hepatitis B virus DNA sequences in the serum of HBsAg-negative patients with chronic liver disease: Transmission of viral particles to chimpanzees. In: Zuckermann AL (ed) Viral hepatitis and liver disease. Liss, New York, pp 553-557 21. Wiese M, Bauer C, Kretzschmar F (1987) Untersuchungen zum krankheitstypischen Schubverhalten der NANB-hepatitis. Dtsch Z Verdau Stoffwechs Krankh 47:14-25 Received: November 26, 1991 Returned for revision: January 14, 1992 Accepted: April 21, 1992 Priv.-Doz. Dr. med. J. Rasenack Medizinische Klinik Albert-Ludwigs Universit/it Hugstetter Strasse 55 W-7800 Freiburg, FRG
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H. Drexler, A. Zeiher, E. Bassenge, H. Just (eds): Endothelial mechanisms of vasomotor control. Steinkopf, Darmstadt 1991. 350 Pages, Hardcover, DM 9 8 , - (ISBN 3-7985-0866-6) The Gargellen Conferences on new developments in cardiovascular research are well known among basic scientists and clinicians as representing the state of the art in modern research. The proceedings of the 1990 Gargellen Conference on endothelian mechanisms of vasomotor control are compiled in this book, which is made up of four parts: 1. Basic physiology of EDRF 2. The endothelium in control of blood flow in vivo 3. Endothelial function in pathological conditions 4. Endothelial function in the clinical setting The introduction (H. Just) on the function of the endothelium, its structure, its function under normal conditions and dysfunction of the dilator mechanism introduces the reader to this difficult subject. The endothelium makes up 2,5 kg in the body, it regulates dilatation and constriction of the blood vessels, and it secretes a variety of vasoactive substances (EDRF, endothelin, fibronectin, interleukin I, tissue plasminogen activator, several growth factors, etc.). Its importance in several dis-
eases (congestive heart failure, syndrome X1 atherosclerosis, hypercholesterolemia, etc.) is the subject of recent research. Possibly the exaggerated NO synthesis of the endothelium is the reason for decreased systemic vascular resistance in septic shock. Certainly, disturbances of endothelial function of a primary or secondary nature are of great clinical significance. Experiments for the better understanding and support of this hypothesis are described in 23 contributions by different authors from all over the world. Each contribution has about 5 to 10 pages containing mainly experimental work on the role of the endothelium on vasomotion and regulation of vascular tone. The papers on endothelial dysfunction in myocardial diseases are of special interest. The reader is confronted with detailed experimental work (isolated blood vessels, isolated endothelium, endothelial cell culture, measurement of coronary flow reserve, etc.). Animal models of coronary artery spasm are used and described as is biochemical work. Also, the role of coronary atherosclerosis and endothelial dysfunction in man is discussed in detail. Progressive endothelial dysfunction even in early stages of atherosclerosis is described. This volume on the 1990 Gargellen Conference is of great interest to all researchers connected with cardiovascular disease, especially with modern views of coronary artery disease. Each contribution gives relevant new literature, there are enough experimental details described to understand the methods, and a short subject index allows one to search for special key words. E. Erdmann (Mfinchen)
Clin Investig (1992) 70:579-584
OriginaJ Article
© Springer-Verlag 1992
Cause and frequency of posttransfusion hepatitis after open-heart surgery H.-J. Schlayer 1, T. Peters 1, S. Preisler ~, H. Berthold 2, W. Gerok ~, and J. Rasenack 1 1 Medizinische Klinik und 2 Hygieneinstitut, Albert-Ludwigs-Universit/it, Freiburg
Summary. A total of 1476 patients who underwent open-heart surgery between 1986 and 1988 participated in a prospective study examining posttransfusion hepatitis. They received a total of 8327 units of whole blood, packed erythrocytes, or fresh frozen plasma. The aminotransferase activities were measured preoperatively and 1, 2, 3, 4, 6, 9, 12, and 24 weeks after the operation. Thirty-four patients in all (2.3 % of the transfused patients) developed posttransfusion hepatitis, which could be identified as hepatitis B in I patient and hepatitis C in 14 patients. No cause for posttransfusion hepatitis could be found in 19 cases (hepatitis of unknown origin). Hepatitis C became chronic in 5 patients. In contrast to hepatitis C, the 19 patients with hepatitis of u n k n o w n origin all showed a milder clinical course with lower maximal aminotransferase activities and a shorter duration of the hepatitis. A chronic course was not observed among them. The cause of hepatitis of unknown origin is discussed.
sion hepatitis cases could not be attributed to any of the known agents [2, 12]. On the basis of epidemiological studies, it was assumed that parenterally transmissible hepatitis non-A non-B could be caused by various infectious viruses [5, 13]. Houghton and his colleagues succeeded in cloning, sequencing, and expressing in vitro of the hepatitis C virus RNA. This enabled the design of an enzyme immune assay which can specifically detect antibodies directed against the hepatitis C virus [6, 15]. The present study was designed to determine the frequency of posttransfusion hepatitis after open-heart surgery at two German cardiosurgical centres. The influence of age, sex, type of operation, and amount of transfused blood units on the frequency of posttransfusion hepatitis was tested. Furthermore, the course as well as the causes of posttransfusion hepatitis were examined.
Posttransfusion hepatitis - Hepatitis B - Hepatitis C - Frequency - Surgery
Methods
Key words:
Posttransfusion hepatitis is still one of the most frequently encountered postoperative complications. Rates of occurence after open-heart surgery of 2% to over 10% have been reported in the literature [2, 3, 7-9, 19]. Until the beginning of the 1970s, the hepatitis B virus infection was the most frequent cause of posttransfusion hepatitis. After the discovery of the hepatitis B virus and the development and use of immunological tests, hepatitis B accounted for only about 10% of posttransfusion hepatitis. The remaining 90% of posttransfuAbbreviations: Hep of UO=hepatitis of unknown origin; ELISA=enzyrne-linked immunosorbent assay; A L A T = a l a nine aminotransferase; ASAT = asparagine aminotransferase; AT=aminotransferase; AT-A=aminotransferase activity; CMV = cytomegalovirus; EBV = Epstein-Barr virus
The 4400 patients of the cardiosurgical centers at Freiburg and Bad Krozingen were approached in the study. Some 90% of the patients agreed to participate; of these 60% received blood transfusions during or immediately after the operation (packed erythrocytes, fresh frozen plasma, or whole blood). Only 63 % of the patients who collaborated proved reliable, so that in all 1476 patients could be analysed. Blood samples were collected preoperatively and 1, 2, 3, 4, 6, 9, 12, and 24 weeks after the operation. Preoperative sera and sera taken 4, 6, 9, 12, and 24 weeks after the operation were tested for aminotransferase activities and bilirubin. The patients were divided into 3 groups based upon their postoperative values. Those with maximum aminotransferase values of 50 U/1 or more were designated as "strongly elevated" ( > 2.5 times the upper limit of normal, group A); patients with maxim u m values between 25 and 49 U/1 (1.25-2.5 times
580 Table 1. Units of blood transfused, number of patients, and average number of units per patient related to postoperative aminotransferase activities
Number of blood units Patients Units per patient
Group A
Group B
Group C
Total
366 (5%) 42 (3%) 8.7
620 (7%) 124 (8%) 5.0
7341 (88%) 1310 (89%) 5.6
8327 (100%) 1476 (100%) 5.6
Group A = strongly elevated aminotransferase activity levels (maximum value > = 50 U/I). Group B = moderately elevated aminotransferase activity levels (maximum value between 25 U/ 1and 49 U/l). Group C = slightly elevated or nonelevated aminotransferase activity levels (maximum value < = 24 U/l). The figures in brackets indicate the distribution into the different groups expressed in percentage
the upper limit of normal, group B) were "moderately elevated"; and patients with maximum values of 24 U/1 or less ( = 15
0 (0%) 1 (1%) 1 (1%) 6 (4%) 9 (6%) 4 (3%) 3 (2%) 4 (3%) 4 (4%) 0 (0%) 0 (0%) 3 (8%) 2 (9%) 0 (0%) 1 (8%) 4 (8%)
Total
42
Group B
Group C
4 (8%) 11 (9%) 19 (11%) 16 (10%) 35 (10%) 18 (11%) 10 (6%) 8 (6%) 7 (6%) 2 (3%) 2 (6%) 4 (11%) I (4%) 2 (22%) 1 (8%) 4 (8%)
Total
48 (92%) 114 (90%) 153 (88%) 142 (86%) 130 (84%) 136 (86%) 153 (92%) 125 (91%) 104 (90%) 60 (97%) 34 (94%) 29 (81%) 20 (87%) 7 (78%) 10 (84%) 45 (84%)
124
52 (100%) 326 (100%) 173 (100%) 164 (100%) 154 (100%) 158 (100%) 166 (100%) 137 (100%) 115 (100%) 62 (100%) 36 (100%) 36 (100%) 23 (100%) 9 (100%) 12 (100%) 53 (100%)
1310
1476
Table 3. Influence of the type of operation (bypass operation or valve replacement) on the postoperative aminotransferase activities Type of operation
Group A
Bypass Valve"
30 (3%) 12 (4%)
Total
42
Group B 88 (8%) 36 (11%) 124
Group C
Total
1023 (89%) 287 (85%)
1141 (100%) 335 (100%)
1310
1476
" No significant difference compared with bypass operations (Z2 test)
Table 4. Influence of the patients' age on postoperative aminotransferase activities Age (years)
Group A
< 59 > =59 a
19 (3%) 23 (3%)
Total
42
Group B
Group C
73 (10%) 51 (7%)
Total
659 (87%) 651 (90%)
124
751 (100%) 725 (100%)
1310
1476
a No significance difference compared with younger age (Xz test)
Table 5. Influence of the patients' sex on postoperative aminotransferase activities Sex
Group A
Male Female"
31 (3%) 11 (5%)
Total
42
Group B 98 (8%) 26 (10%) 124
Group C
Total
1084 (89%) 226 (85%)
1213 (100%) 263 (100%)
1310
1476
" No significant difference compared with male sex (22 test)
and patients with hepatitis of unknown origin received 7.2_+5.6 blood units. The difference was statistically insignificant. The severity and length of posttransfusion hepatitis are summarized in Table 7. Ten of 14 patients
with newly acquired hepatitis C showed peak aminotransferase activity levels of more than 100 U/1 during the 6-month observation period. Ten of 14 patients with newly acquired hepatitis C revealed aminotransferase activities elevated
582 Table 6. Causes of strongly elevated aminotransferase (AT) activity levels in group A
Table 8. Cause of moderately elevated aminotransferase activity
New infection, hepatitis B New infection, hepatitis C Preexisting hepatitis C Ethanol Preoperative elevation of AT activity Unidentified cause
1 14 4 1 3 19
Preexisting hepatitis B New infection, hepatitis C Preexisting hepatitis C Unidentified cause
1 4 4 115
Total
124
Total
42
Table 7. Severity and length of posttransfusion hepatitis.
Above,
peak aminotransferase activity (AT-A) levels related to the dignosis of hepatitis B, hepatitis C, and hepatitis of unknown origin (Hep of UO). Middle, duration of aminotransferase activity elevation related to the diagnosis of hepatitis B, hepatitis C, and hepatitis of unknown origin. Patients with aminotransferase activity levels greater or equal to 50 U/1 at two or more postoperative controls were designated as "several AT-A > = 50 U/1." Patients with an aminotransferase activity level greater or equal to 50 U/1 at a single postoperative control were designated as "single AT-A > = 50 U/1." Below, number of patients with an aminotransferase activity (AT-A) level of more than 20 U/1 2 years after the operation related to the diagnosis of hepatitis B, hepatitis C, and hepatitis of unknown origin Hep B
Hep C
Hep of UO
Peak AT-A > 100 U/1 Peak AT-A < = 100 U/1 Sum
1 0 1
10 4 14
1 18 19
Several AT-A > = 50 U/1 Single AT-A > = 50 U/1 Sum
0 1 1
10 4 14
1 18 19
AT-A2 y.aft.op. > 20 U/1 AT-A 2 y..ft.op. < = 20 U/1 Sum
0 1 1
5 7 12"
0 19 19
" Two patients had died
more than 2.5 times the upper limit of normal over several postoperative controls. In 5 of 14 patients with newly acquired hepatitis C, pathological aminotransferase activity levels were still found 2 years after the operation. In contrast, the patients with hepatitis of u n k n o w n origin showed a more favourable course: Only 1 of 19 patients reached maximum aminotransferase activity levels of more than 100 U/l, 1 of 19 patients had an aminotransferase activity elevated more than 2.5 times over the upper limit of normal several times, and 2 years after the operation all patients exhibited normalized liver enzyme activities. The cause of the moderately elevated aminotransferase activity levels of the patients in group B are summarized in Table 8. Four patients were newly infected with the hepatitis C virus. Preexistent hepatitis C infection could be diagnosed in
levels in group B
4 patients, and preexisting hepatitis B was found in 1 patient. In 115 patients, the cause of the moderately elevated aminotransferase activity levels is unknown. Discussion
The present study examines the cause and frequency of acute posttransfusion hepatitis. The aminotransferase activities (asparagine and alanine, ASAT and ALAT) were measured between the 4th and the 24th weeks postoperatively in 1476 patients, who had received a total of 8327 units of blood during or immediately after open heart surgery. Forty-two patients showed aminotransferase activities elevated more than 2.5 times the upper limit of normal (group A). After subtracting patients with preexisting liver disease (preexisting hepatitis C, ethanol consumption, preexisting liver disease of u n k n o w n cause), posttransfusion hepatitis was indicated for 34 patients from group A. If one adds the 4 patients with newly contracted hepatitis C from group B, the number of patients with posttransfusion hepatitis rises to 38. Therefore, the frequency of posttransfusion hepatitis is 2.6%. This value is comparable with findings from England [7], The Netherlands [19], France [3], and Australia [9]. The frequency of posttransfusion hepatitis in the countries above is considerably lower than in the U S A [2] and Italy [8], where frequencies of 10% were reached. As expected, the age and sex of the patient and the type of operation (valve or bypass) had no influence on membership in group A. There tended to be a relationship between the number of blood transfusions and membership of group A, but the Wilcoxon rank sum test proved not significant at a limit of 5%. This could be explained by an unknown stratification (e.g., infection by a donor with a rare blood group). In the literature, the portion of hepatitis C in chronic posttransfusion hepatitis is stated as between 59% and 84% [10, 14-16, 18]. On the other hand, the portion of hepatitis C in acute resolving posttransfusion hepatitis is reported at between 15% and 25% [15, 18]. The present examination
583 included all patients with acute and chronic posttransfusion hepatitis w i t h o u t consideration o f the further course. I f the 4 patients with newly contracted hepatitis C f r o m g r o u p B are added to the 14 patients f r o m g r o u p A, the p o r t i o n o f hepatitis C in p o s t t r a n s f u s i o n hepatitis a m o u n t s to 4 7 % (18 o f 38 patients). Raised levels o f aminotransferase activities 2 years after the operation, reflecting the developm e n t o f chronic hepatitis, were observed in 5 o f 38 patients with posttransfusion hepatitis. All these patients had a n t i - H C V antibodies, so that the portion o f hepatitis C in chronic posttransfusion hepatitis rises to up to 100%. Thus, the present examination agrees with the literature. The clinical course o f hepatitis C is characterized by a frequent transition to chronic hepatitis. In the present study, 5 o f 18 patients who contracted hepatitis C became chronic, c o r r e s p o n d i n g to 28%, However, the actual figure might be higher for two reasons: (1) Sera o f two patients who had died were not available 2 years after the operation. (2) F l u c t u a t i o n s o f the aminotransferase activity levels; up to tenfold variations within a few days have been r e p o r t e d for hepatitis C [21]. In c o n t r a s t to hepatitis C, the 19 patients with hepatitis o f u n k n o w n origin showed a milder clinical course. This can be deduced f r o m the lower m a x i m u m aminotransferase activity levels and the shorter d u r a t i o n o f the hepatitis. A chronic course was not observed. Several causes o f hepatitis o f u n k n o w n origin are conceivable: In I patient, posttransfusion hepatitis caused by the hepatitis B virus was detected. M u t a n t s o f the hepatitis B virus with a very low antigenic concentration in the serum or m u t a n t s with changes o f their antigenic structure m a y escape traditional immunological detection. P r o o f o f H B V - D N A in the serum o f patients with H B s A g negative chronic hepatitis has been described in the literature [20]. It is also conceivable that m u t a n t s o f the hepatitis C virus which c a n n o t be detected by the present tests are responsible for hepatitis o f u n k n o w n origin. This seems possible as the antigens o f the hepatitis C virus have not yet been sufficiently characterized and since R N A viruses tend to high mutation rates. - In the older literature, two different N A N B viruses with different biochemical properties and inc u b a t i o n times have been described [1, 4, 11, 17]. A n a n t i - H C V seroconversion only occurs for 1 5 % - 2 5 % o f acute, healing posttransfusion hepatitis [15, 20]. Thus, the acute, healing posttransfusion hepatitis could also be caused by a different virus, n o t yet identified. -
-
Acknowledgements. We wish to thank the staff of the Chirurgische Universit/itsklinik, Abteilung ffir Herz- und Gef~gchirurgie, Albert-Ludwigs-Universit/it, Freiburg, and the staff of the Benedikt Kreutz Rehabilitationszentrum, Bad Krozingen, for their help and assistance during the study period and J. Fehr, M. Falasca, and H. Bexter for their technical assistance.
R e f e r e n c e s
1. Aach RD, Lander JJ!: Shermann LA (1978) Transfusion transmitted viruses: interim analysis of hepatitis among transfused and nontransfused patients. In: Vyas GN, Cphen SH, Schmid R (eds) Viral hepatitis, a contemporary assessment of etiology, epidemiotogy, pathogenesis and prevention. Franklin Institute Press, Philadelphia, pp 383-396 2. Alter HJ, Purcell RH, Holland PV, Feinstone SM, Morrow AG, Moritsugu Y (1975) Clinical and serological analysis of transfusion-associated hepatitis. Lancet II: 838-841 3. Aymard JP, Janot C, Gayet S, Guillemin C, Canton P, Gaucher P, Streiff F (1986) Post-transfusion non-A, non-B hepatitis after cardiac surgery. Vox Sang 51:236-238 4. Bradley DW, Maynard JE, Popper H, Cook EH, Ebert JE, McCaustland KA, Schable CA, Fields HA (1983) Posttransfusion non-A, non-B hepatitis: physicochemical properties of two distinct agents. J Infect Dis 148:254-265 5. Bradley DW, McCaustland KA, Cook EH, Schable CA, Ebert JW, Maynard JE (1985) Posttransfusion non-A, nonB hepatitis in chimpanzees. Physiochemical evidence that the tubule-forming agent is a small, enveloped virus. Gastroenterology 88 : 773-779 6. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:35%362 7. Collins JD, Bassendine MF, Codd AA, Collins A, Ferner RE, James OFW (1983) Prospective study of post-transfusion hepatitis after cardiac surgery in a British centre. Br Med J 287:1422-1424 8. Colombo M, Oldani S, Donato MF, Borzio M, Santese R, Roffi L, Vigano P, Cargnel A (1987) A multicenter study of posttransfusion hepatitis in Milan. Hepatology 7:709712 9. Cossart YE, Kirsch S, Ismay SL (1982) Post-transfusion hepatitis in Australia. Lancet I:208-213 10. Courouce AM, Jullien AM, Vedrenne JB, Habibi B (1990) Anti-hepatitis C antibodies in prospectively followed-up transfused patients. Vox Sang 58 : 226-227 11. Craske J, Dilling N, Stern D (1975) An outbreak of hepatitis associated with intravenous injection of factor VIII concentrate. Lancet II : 221-223 12. Feinstone SM, Kapikain AZ, Purcell RH et al. (1975) Transfusion-associated hepatitis not due to hepatitis type A or B. N Engl J Med 292:767-770 13. He LF, Alling D, Popkin T, Shapiro M, Alter HJ, Purcell RH (1987) Determining the size of non-A, non-B hepatitis virus by filtration. J Infect Dis 156:636-640 14. Hopf U, MSller B, Kfither D, Stemerowicz R, Lobeck H, Lfidtke-Handjery A, Walter E, Blum HE, Roggendorf M, Deinhardt F (1990) Long-term follow-up of posttransfusion and sporadic chronic hepatitis non-A, non-B and frequency of circulating antibodies to hepatitis C virus (HCV). J Hepatol 10 : 69-76 15. Kuo G, Choo QL, Alter H J, Gitnik GL, Redeker AG, Purceil RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Yegtmeier TE, Bonino F, Colombo M, Lee WS, Kuo C, Berger K, Shuster JR, Overby LR, Bradley DW, Houghton
584 M (1989) An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362-364 16. Mattsson L, Weiland O, Glaurnann H (1990) Application of a numerical scoring system for assessment of histological outcome in patients with chronic posttransfnsion non-A, non-B hepatitis with or without antibodies to hepatitis C. Liver 10:257-263 17. Mosey JW, Redeker AG, Feinstone SM, Purcell RH (1977) Multiple hepatitis viruses in multiple attacks of acute viral hepatitis. N Engl J Med 296:75-78 18. Poel CL van der, Reesink HW, Lelie PN, LeentvaarKuypers A, Choo QL, Kuo G (1989) Anti-hepatitis C antibodies and non-A, non-B post-transfusion hepatitis in The Netherlands. Lancet I1:297-299 19. Reesink HW, Leentvaar-Kuypers A, Poel CL van der, Lelie PN, Pietersz RNI, Mulder-Folkerts DKF, Pieters T, Ende A van den, Schaasberg W, Coutinho RA (1988) Non-A, non-B posttransfusion hepatitis in open heart surgery patients in The Netherlands : preliminary results of a prospective study. In: Zuckermann AL (ed) Viral hepatitis and liver disease. Liss, New York, pp 553-557
20. Thiers V, Fujita Y, Takahashi H, Schellekens H, Reus A de, Driss F, Degott C, Isselbacher K, Tiollais P, Wands J, Brechot C (1988) Hepatitis B virus DNA sequences in the serum of HBsAg-negative patients with chronic liver disease: Transmission of viral particles to chimpanzees. In: Zuckermann AL (ed) Viral hepatitis and liver disease. Liss, New York, pp 553-557 21. Wiese M, Bauer C, Kretzschmar F (1987) Untersuchungen zum krankheitstypischen Schubverhalten der NANB-hepatitis. Dtsch Z Verdau Stoffwechs Krankh 47:14-25 Received: November 26, 1991 Returned for revision: January 14, 1992 Accepted: April 21, 1992 Priv.-Doz. Dr. med. J. Rasenack Medizinische Klinik Albert-Ludwigs Universit/it Hugstetter Strasse 55 W-7800 Freiburg, FRG
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H. Drexler, A. Zeiher, E. Bassenge, H. Just (eds): Endothelial mechanisms of vasomotor control. Steinkopf, Darmstadt 1991. 350 Pages, Hardcover, DM 9 8 , - (ISBN 3-7985-0866-6) The Gargellen Conferences on new developments in cardiovascular research are well known among basic scientists and clinicians as representing the state of the art in modern research. The proceedings of the 1990 Gargellen Conference on endothelian mechanisms of vasomotor control are compiled in this book, which is made up of four parts: 1. Basic physiology of EDRF 2. The endothelium in control of blood flow in vivo 3. Endothelial function in pathological conditions 4. Endothelial function in the clinical setting The introduction (H. Just) on the function of the endothelium, its structure, its function under normal conditions and dysfunction of the dilator mechanism introduces the reader to this difficult subject. The endothelium makes up 2,5 kg in the body, it regulates dilatation and constriction of the blood vessels, and it secretes a variety of vasoactive substances (EDRF, endothelin, fibronectin, interleukin I, tissue plasminogen activator, several growth factors, etc.). Its importance in several dis-
eases (congestive heart failure, syndrome X1 atherosclerosis, hypercholesterolemia, etc.) is the subject of recent research. Possibly the exaggerated NO synthesis of the endothelium is the reason for decreased systemic vascular resistance in septic shock. Certainly, disturbances of endothelial function of a primary or secondary nature are of great clinical significance. Experiments for the better understanding and support of this hypothesis are described in 23 contributions by different authors from all over the world. Each contribution has about 5 to 10 pages containing mainly experimental work on the role of the endothelium on vasomotion and regulation of vascular tone. The papers on endothelial dysfunction in myocardial diseases are of special interest. The reader is confronted with detailed experimental work (isolated blood vessels, isolated endothelium, endothelial cell culture, measurement of coronary flow reserve, etc.). Animal models of coronary artery spasm are used and described as is biochemical work. Also, the role of coronary atherosclerosis and endothelial dysfunction in man is discussed in detail. Progressive endothelial dysfunction even in early stages of atherosclerosis is described. This volume on the 1990 Gargellen Conference is of great interest to all researchers connected with cardiovascular disease, especially with modern views of coronary artery disease. Each contribution gives relevant new literature, there are enough experimental details described to understand the methods, and a short subject index allows one to search for special key words. E. Erdmann (Mfinchen)
