A study on the TNF-alpha system in Caucasian Spanish patients with alcoholic liver disease.
BACKGROUND
Tumor necrosis factor-alpha (TNF-alpha) is thought to be a critical driving force of inflammatory damage in alcoholic liver disease (ALD). We aimed to establish whether there is a correlation between plasma levels of the soluble TNF-alpha receptors 1 and 2 (sTNFR1 and sTNFR2) and the severity of liver damage in patients with ALD. We also aimed to elucidate whether functionally active polymorphisms in the promoter region of the TNF-alpha gene modulate the development of ALD.


METHODS
We studied 614 Spaniards. Of these, 278 were alcoholics (103 without liver histologic abnormalities, 89 with non-cirrhotic liver disease and 86 with cirrhosis) and 336 were non-alcoholics (115 healthy controls, 114 with non-alcoholic non-cirrhotic liver disease and 107 with cirrhosis unrelated to alcohol). Plasma levels of sTNFR1 and sTNFR2 were determined by ELISA and results were expressed in ng/mL and subsequently converted in log(10). TNF-alpha gene promoter region polymorphisms at the positions -238, -308 and -863 were assessed by restriction fragment length polymorphisms (RFLPs) on white cell DNA. Differences in plasma sTNFR1 and sTNFR2 levels between groups were compared with the one-way and two-factor analysis of variance test, and Student's t-test. Genotype distribution and allele frequencies in the different groups were compared using the chi(2) test or Fisher's exact test.


RESULTS
sTNFR1 and sTNFR2 plasma levels were significantly higher in patients with cirrhosis than in those with non-cirrhotic liver disease (p<0.001) and individuals without liver disease (p<0.001), both in the alcoholic and the non-alcoholic group. Among cirrhotics, sTNFR1 and sTNFR2 levels had a significant positive correlation with the severity of the liver disease, graded with the Child-Pugh's score (p=0.003 and p<0.001, respectively). TNF-alpha genotype distribution and allele frequencies of the three loci assessed were similar in the groups studied, hence no particular genotype or haplotype could be linked to ALD.


CONCLUSIONS
The TNF-alpha system is activated in patients with cirrhosis of the liver irrespective of aetiology. TNF-alpha polymorphisms at positions -238, -308 and -863 are not linked to ALD.
Auguet
Teresa
T
Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Universitat Rovira i Virgili, Tarragona, Spain. tauguet.hj23.ics@gencat.net
Vidal
Francesc
F
López-Dupla
Miguel
M
Broch
Montserrat
M
Gutiérrez
Cristina
C
Olona
Montserrat
M
Oltra
Carmina
C
Aguilar
Carmen
C
González
Eva
E
Quer
Joan-Carles
JC
Sirvent
Joan-Josep
JJ
Richart
Cristóbal
C
D000368:Aged; D000428:Alcohol Drinking / Q000523:psychology; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood / Q000235:genetics; D013030:Spain / Q000453:epidemiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D044465:White People
D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D004247:DNA