Zusammenfassung
Bei Patienten mit Leberzirrhose lässt sich eine Reihe
unterschiedlicher Fehlfunktionen im Immunsystem nachweisen. Diese betreffen
sowohl die unspezifische Abwehr als auch die antigenspezifischen Reaktionen.
Sehr gut untersucht und in seiner klinischen Bedeutung gut belegt ist die
eingeschränkte Leistung des retikuloendothelialen Systems bei
Leberzirrhose. Hier zeigt sich ein enger Zusammenhang zur Inzidenz bakterieller
Infektionen und zur Prognose der Patienten. Andere Störungen wie die
eingeschränkte Funktion neutrophiler Granulozyten sind wahrscheinlich
für den klinischen Verlauf eher sekundär. Ob die gestörte
Aktivierung der Natural-Killerzellen (NK-Zellen) und der lymphokinaktivierten
Killerzellen (LAK-Zellen) eine Prädisposition für die Entwicklung
eines hepatozellulären Karzinoms bei Leberzirrhose darstellt, müssen
weitere Studien zeigen. Auffällig ist ein mäßig vermindertes
Ansprechen auf Impfungen bei Leberzirrhose, was bei den meisten Impfstoffen
aber durch eine Dosiserhöhung ausgeglichen werden kann.
Function of the immune system in liver cirrhosis
Malfunction of the immune system at different levels is typical for
patients with liver cirrhosis. Both non-specific as well as antigen-specific
functions may be compromised. The best studied and clinically most important
problem is the diminished clearance capacity of the reticulo-endothelial system
in liver cirrhosis. This transfers into a significantly higher rate of
bacterial infections associated with a poorer prognosis in these patients. The
clinical relevance of concomitant immune disorders like neutrophil dysfunction
is less clear. An impaired activation of natural killer cells (NK) and
lymphokine-actvated killer cells (LAK) may have a role in the development of
hepatocellular carcinoma but additional studies are needed. Clinically
important is a moderately reduced efficacy of standard immunization protocols,
which can be overcome by an increased dose in most vaccines.
Schlüsselwörter
Immunsystem - Leberzirrhose - Infektionen - Makrophagen - RES - neutrophile
Granulozyten - Natural-Killerzellen - Lymphozyten - Opsonine - Impfungen
Key words
Immune System - Liver
Cirrhosis - Infections - Macrophages - RES - Neutrophile
Granulocytes - Natural Killer
Cells - Lymphocytes - Opsonines - Vaccination
Literatur
-
1
Runyon B A.
Bacterial infections in patients with
cirrhosis.
J Hepatol.
1993;
18
271-272
-
2
Beutler B A, Milsark I W, Cerami A.
Cachectin/tumor necrosis factor: Production, distribution,
and metabolic fate in
vivo.
J Immunol.
1985;
135
3972-3977
-
3
Castell J V, Geiger T, Gross V. et al .
Plasma clearance, organ distribution and target cells of
interleukin-6/hepatocytestimulating factor in the rat.
Eur J
Biochem.
1988;
177
357-361
-
4
Ferraiolo B L, Moore J A, Crase D. et al .
Pharmacokinetics and tissue distribution of recombinant human
tumor necrosis factor-alpha in mice.
Drug Metab
Dispos.
1988;
16
270-275
-
5
Klapproth J, Castell J, Geiger T, Andus T, Heinrich P C.
Fate and biological action of human recombinant interleukin
1beta in the rat in vivo.
Eur J
Immunol.
1989;
19
1485-1490
-
6
Sonne O, Davidson O, Møller B K, Munck P etersen
C.
Cellular targets and receptors for interleukin-6: I. In vivo
and in vitro uptake of IL-6 in liver and hepatocytes.
Eur J Clin
Invest.
1990;
20
366-370
-
7 Wisse E, Braet F, Luo D. et al .Sinusoidal liver cells. Oxford Textbook of Clinical
Hepatology, 2nd edition (Bircher J, Benhamou JP, McIntyre N, Rizetto M,
Rodés J) Oxford; Oxford University
Press 1999: 33-50
-
8
van Bossuyt H, de
Zanger R B, Wisse E.
Cellular and subcellular distribution of injected
lipopolysaccharide in rat liver and its inactivation by bile salts.
J
Hepatol.
1988;
7
325-327
-
9
Wisse E, Luo D, Vermijlen D. et al .
On the function of pit cells, the liver-specific natural
killer cells.
Semin Liver
Dis.
1997;
17
265-286
-
10 McCormick P A. The spleen, hypersplenism and other relationships between the
liver and the spleen. Oxford Textbook of Clinical Hepatology, 2nd
edition (Bircher J, Benhamou JP, McIntyre N, Rizetto M, Rodés
J) Oxford; Oxford University
Press 1999: 787-795
-
11
Shah S H, Hayes P C, Allan P L, Nicoll J, Finlayson N D.
Measurement of spleen size and its relation to hypersplenism
and portal hemodynamics in portal hypertension due to hepatic
cirrhosis.
Am J
Gastroenterol.
1996;
91
2580-2583
-
12
Rozga J, Jeppsson B, Hagerstrand I, Bengmark S.
Acute portal vein stenosis. An experimental study on portal
circulation and hepatosplenic function.
Acta Chir
Scand.
1985;
151
125-131
-
13
el-Khishen M A, Henderson J M, Millikan W J
Jr, Kutner M H, Warren W D.
Splenectomy is contraindicated for thrombocytopenia secondary
to portal hypertension.
Surg Gynecol
Obstet.
1985;
160
233-238
-
14
Mbopi-Keou F X, Belec L, Lavril M. et al .
Severe lymphopenia as a predictive marker for peritoneal
infection in alcoholic cirrhosis.
Eur J
Med.
1992;
1
317-318
-
15 Gerok W, Rössle M, Schölmerich J. Leberzirrhose. Gerok W, Blum
HE Hepatologie 2.
Aufl München; Urban &
Schwarzenberg 1995: 322-375
-
16
Tomino S, Fujiwara H, Kagimoto T. et al .
Decreased suppressor T cell activity in patients with hepatic
cirrhosis.
Clin Exp
Immunol.
1982;
48
625-632
-
17
Holdstock G, Ershler WB, Krawitt E L.
Demonstration of non-specific B-cell stimulation in patients
with
cirrhosis.
Gut.
1982;
23
724-728
-
18
Simon G, Gorbach S L.
Intestinal flora in health and
disease.
Gastroenterology.
1984;
86
174-193
-
19
Lai D, Gorbach S L, Levitan R.
Intestinal microflora in patients with alcoholic cirrhosis:
Urea-splitting bacteria and neomycin
resistance.
Gastroenterology.
1972;
62
275-279
-
20
Martini G A, Phear E A, Ruebner E, Sherlock S.
The bacterial content of the small intestine in normal and
cirrhotic subjects: Relation to methionine toxicity.
Clin
Sci.
1956;
16
35-51
-
21
Morencos F C, de
las H eras Castano G. et al .
Small bowel bacterial overgrowth in patients with alcoholic
cirrhosis.
Dig Dis
Sci.
1995;
40
1252-1256
-
22
Yang C Y, Chang C S, Chen G H.
Small-intestinal bacterial overgrowth in patients with liver
cirrhosis, diagnosed with glucose H2 or CH4 breath tests.
Scand J
Gastroenterol.
1998;
33
867-871
-
23
Llovet J M, Bartoli R, Planas R. et al .
Bacterial translocation in cirrhotic rats. Its role in the
development of spontaneous bacterial
peritonitis.
Gut.
1994;
35
1648-1652
-
24
Runyon B A, Squier S, Borzio M.
Translocation of gut bacteria in rats with cirrhosis to
mesenteric lymph nodes partially explains the pathogenesis of spontaneous
bacterial peritonitis.
J
Hepatol.
1994;
21
792-796
-
25 Rimola A, Navasa M. Infections in liver disease. Oxford Textbook of
Clinical Hepatology, 2nd edition (Bircher J, Benhamou JP, McIntyre N, Rizetto
M, Rodés J) Oxford; Oxford University
Press 1999: 1861-1874
-
26
Garcia-Tsao G, Lee F Y, Barden G E, Cartun R, West A B.
Bacterial translocation to mesenteric lymph nodes is
increased in cirrhotic rats with
ascites.
Gastroenterology.
1995;
108
1835-1841
-
27
Sorell W T, Quigley E MM, Jin G, Johnson T J, Rikkers L F.
Bacterial translocation in the portal-hypertensive rat:
Studies in basal conditions and on exposure to hemorrhagic
shock.
Gastroenterology.
1993;
104
1722-1726
-
28
Campillo B, Pernet P, Bories P N. et al .
Intestinal permeability in liver cirrhosis: relationship with
severe septic complications.
Eur J Gastroenterol
Hepatol.
1999;
11
755-759
-
29
Caly W R, Strauss E.
A prospective study of bacterial infections in patients with
liver cirrhosis.
J
Hepatol.
1993;
18
353-358
-
30
Graudal N, Milman N, Kirkegaard E, Korner B, Thomsen A C.
Bacteremia in cirrhosis of the
liver.
Liver.
1986;
6
297-301
-
31
Navasa M, Rimola A, Rodés J.
Bacterial infections in liver disease.
Semin Liver
Dis.
1997;
17
323-333
-
32
Horan T C, White J W, Jarvis W R. et al .
Nosocomial infection surveillance, 1984.
Morb
Mortal Wkly Rep CDC Surveill
Summ.
1986;
35
17SS-29SS
-
33
EPINE W orking Group.
Prevalence of hospital-acquired infection in
Spain.
J Hosp
Infect.
1992;
20
1-13
-
34
Dinkel R H, Lebok U.
A survey of nosocomial infections and their influence on
hospital morality rates.
J Hosp
Infect.
1994;
28
297-304
-
35
Kuo C H, Changchien C S, Yang C Y, Sheen I S, Liaw Y F.
Bacteremia in patients with cirrhosis of the
liver.
Liver.
1991;
11
334-339
-
36
Deschenes M, Villeneuve J P.
Risk factors for the development of bacterial infections in
hospitalized patients with cirrhosis.
Am J
Gastroenterol.
1999;
94
2193-2197
-
37
Runyon B A, Morrissey R L, Hoefs J C, Wyle F A.
Opsonic activity of human ascitic fluid: A potentially
important protective mechanism against spontaneous bacterial
peritonitis.
Hepatology.
1985;
5
634-637
-
38
Runyon B A.
Low-protein-concentration ascitic fluid is predisposed to
spontaneous bacterial
peritonitis.
Gastroenterology.
1986;
91
1343-1346
-
39
Runyon B A.
Patients with deficient ascitic fluid opsonic activity are
predisposed to spontaneous bacterial
peritonitis.
Hepatology.
1988;
8
632-635
-
40
Rimola A, Soto R, Bory F. et al .
Reticuloendothelial system phagocytic activity in cirrhosis
and its relation to bacterial infections and
prognosis.
Hepatology.
1984;
4
53-58
-
41
Bolognesi M, Merkel C, Bianco S. et al .
Clinical significance of the evaluation of hepatic
reticuloendothelial removal capacity in patients with
cirrhosis.
Hepatology.
1994;
19
628-634
-
42
Guarner C, Runyon B A.
Macrophage function in cirrhosis and the risk of bacterial
infection.
Hepatology.
1995;
22
367-369
-
43
Gomez F, Ruiz P, Schreiber A D.
Impaired function of macrophage Fc-gamma receptors and
bacterial infection in alcoholic cirrhosis.
New Engl J
Med.
1994;
331
1122-1128
-
44
Fox R A, Dudley F J, Sherlock S.
The serum concentration of the third component of complement
beta-1C-beta-1A in liver
disease.
Gut.
1971;
12
574-578
-
45
Kourilsky O, LeRoy C, Peltier A P.
Complement and liver cell function in 53 patients with liver
disease.
Am J
Med.
1973;
55
783-790
-
46
Llach J, Rimola A, Navasa M. et al .
Incidence and predictive factors of first episode of
spontaneous bacterial peritonitis in cirrhosis with ascites: Relevance of
ascitic fluid protein
concentration.
Hepatology.
1992;
16
724-727
-
47
Tito L, Rimola A, Gines P. et al .
Recurrence of spontaneous bacterial peritonitis in cirrhosis:
Frequency and predictive
factors.
Hepatology.
1988;
8
27-31
-
48
Altin M, Rajkovik I A, Hughes R D, Williams R.
Neutrophil adherence in chronic liver disease and fulminant
hepatic
failure.
Gut.
1983;
24
746-750
-
49
DeMeo A N, Andersen B R.
Defective chemotaxis associated with a serum inhibitor in
cirrhotic patients.
New Engl J
Med.
1972;
286
735-740
-
50
Feliu E, Gougerot M A, Hakim J. et al .
Blood polymorphonuclear dysfunction in patients with
alcoholic cirrhosis.
Eur J Clin
Invest.
1977;
7
571-577
-
51
Maderazo E C, Ward P A, Quintiliani R.
Defective regulation of chemotaxis in cirrhosis.
J
Lab Clin
Med.
1975;
85
621-360
-
52
Rajkovic I A, Williams R.
Abnormalities of neutrophil phagocytosis, intracellular
killing and metabolic activity in alcoholic cirrhosis and
hepatitis.
Hepatology.
1986;
6
252-262
-
53
Uehara M, Sato N.
Impaired ability of neutrophils to produce oxygen-derived
free radicals in patients with chronic liver disease and hepatocellular
carcinoma.
Hepatology.
1994;
20
326-330
-
54
Garcia-González M, Boixeda D, Herrero D, Burgaleta C.
Effect of granulocyte-macrophage colony-stimulating factor on
leukocyte function in
cirrhosis.
Gastroenterology.
1993;
105
527-531
-
55
Yousif-Kadaru A GM, Rajkovik I A, Wyke R J, Williams R.
Defects in serum attractant activity in different types of
chronic liver
disease.
Gut.
1984;
25
79-84
-
56
Chuang W L, Liu H W, Chang W Y. et al .
Natural killer cell activity in patients with liver cirrhosis
relative to severity of liver damage.
Dig Dis
Sci.
1991;
36
299-302
-
57
Hirofuji H, Kakumu S, Fuji A. et al .
Natural killer and activated killer activities in chronic
liver disease and hepatocellular carcinoma: Evidence for a decreased
lymphokine-induced activity of effector cells.
Clin Exp
Immunol.
1987;
68
348-356
-
58
Nakamura T, Morizane T, Watanabe T. et al .
Decreased natural killer activity in patients with liver
cirrhosis.
Int J
Cancer.
1983;
32
573-575
-
59
Ledesma F, Echevarria S, Casafont F, Lozano J L, Pons-Romero F.
Natural killer cell activity in alcoholic cirrhosis:
Influence of nutrition.
Eur J Clin
Nutr.
1990;
44
733-740
-
60
Nichigaki Y, Ohnishi H, Moriwaki H, Muto Y.
Ursodeoxycolic acid corrects defective natural killer
activity by inhibiting prostaglandin E2 production in primary biliary
cirrhosis.
Dig Dis
Sci.
1996;
41
1487-1493
-
61
Shirachi M, Sata M, Miyajima I, Tanaka M, Tanikawa K.
Liver-associated natural killer activity in cirrhotic
rats.
Microbiol
Immunol.
1998;
42
117-124
-
62
Saibara T, Maeda T, Miyazaki M, Onishi S, Yamamoto Y.
Depressed immune function in patients with cirrhosis before
emergence of hepatocellular
carcinoma.
Hepatology.
1993;
18
315-319
-
63
Hsu C CS, Leevy C M.
Inhibition of PHA-stimulated lymphocyte transformation by
plasma from patients with advanced alcoholic cirrhosis.
Clin Exp
Immunol.
1971;
8
749-760
-
64
Nouri-Aria K T, Alexander G JM, Portmann B C. et al .
T and B cell function in alcoholic liver disease.
J
Hepatol.
1986;
2
195-207
-
65
Schirren C A, Jung M C, Zachoval R. et al .
Analysis of T cell activation pathways in patients with liver
cirrhosis, impaired delayed hypersensitivity and other T cell-dependent
functions.
Clin Exp
Immunol.
1997;
108
144-150
-
66
Franco D, Charra M, Jeambrun P. et al .
Nutrition and immunity after peritoneovenous drainage of
intractable ascites in cirrhotic patients.
Am J
Surg.
1983;
146
652-657
-
67
O’Keefe S J, El-Zayadi A R, Carraher T E, Davis M, Williams R.
Malnutrition and immuno-incompetence in patients with liver
disease.
Lancet.
1980;
ii
615-617
-
68
Hirsch S, de la
Marza M P, Gattas V. et al .
Nutritional support in alcoholic cirrhotic patients improves
host defenses.
J Am Coll
Nutr.
1999;
18
434-441
-
69
Keeffe E B, Iwarson S, McMahon B J. et al .
Safety and immunogenicity of hepatitis A vaccine in patients
with chronic liver
disease.
Hepatology.
1998;
27
881-886
-
70
Keeffe E B, Krause D S.
Hepatitis B vaccination of patients with chronic liver
disease.
Liver Transpl
Surg.
1998;
4
437-439
-
71
McCashland T M, Preheim L C, Gentry-Nielsen M J.
Pneumococcal vaccine response in cirrhosis and liver
transplantation.
J Infect
Dis.
2000;
181
757-760
-
72
Villeneuve E, Vincelette J, Villeneuve J P.
Ineffectiveness of hepatitis B vaccination in cirrhotic
patients waiting for liver transplantation.
Can J
Gastroenterol.
2000;
14 Suppl.
B
59B-62B
-
73
Wiedmann M, Liebert U G, Oesen U. et al .
Decreased immunogenicity of recombinant hepatitis B vaccine
in chronic hepatitis
C.
Hepatology.
2000;
31
230-234
-
74
De
Maria N, Idilman R, Colantoni A, Harig J M, Van
Thiel D H.
Antibody response to hepatitis B virus vaccination in
individuals with hepatitis C virus
infection.
Hepatology.
2000;
32
444-445
-
75
Dominguez M, Barcena R, Garcia M, Lopez-Sanroman A, Nuno J.
Vaccination against hepatitis B virus in cirrhotic patients
on liver transplant waiting list.
Liver
Transpl.
2000;
6
440-442
-
76
Horlander J C, Boyle N, Manam R. et al .
Vaccination against hepatitis B in patients with chronic
liver disease awaiting liver transplantation.
Am J Med
Sci.
1999;
318
304-307
Prof. Dr. med. Michael P. Manns
Direktor der Abteilung Gastroenterologie und
Hepatologie
Medizinische Hochschule Hannover
Carl-Neuberg-Straße 1
30623 Hannover
eMail: Manns.michael@mh-hannover.de