Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection

Abstract

Abstract Abstract AbstractAIM: Clinical and experimental data suggest that gut-derived endotoxins are an important pathogenic factors for progression of chronic liver disease. Recently, a C-T (-159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression and to be associated with advanced alcoholic liver damage. Here, we investigated this polymorphism in patients with less advanced alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection. METHODS:CD14 genotyping was performed by PCR-RFLP analysis in (a) 121 HCV patients, (b) 62 patients with alcohol-associated cirrhosis (Alc-Ci), (c) 118 individuals with heavy alcohol abuse without evidence of advanced liver damage (Alc-w/o Ci), and (d) 247 healthy controls. Furthermore, serum levels of soluble CD14 (sCD14) and transaminases were determined. RESULTS:The TT genotype was significantly more frequent in Alc-Ci compared to Alc-w/o Ci or controls (40.3% vs 23.7% or 24.0%, respectively). In Alc-w/o Ci, serum levels of transaminases did not differ significantly between patients with different CD14 genotypes. In HCV patients, TT-homozygotes had significantly higher sCD14 levels and sCD14 serum levels were significantly higher in patients with advanced fibrosis or cirrhosis. However, no association was found between CD14 genotypes and histological staging or grading. CONCLUSION:Considering serum transaminases as surrogate markers for alcoholic liver damage, the CD14 polymorphism seems to exhibit different effects during the course of ALD. Differences in genotype distribution between cirrhotic HCV patients and alcoholics and the known functional impact of this polymorphism on CD14 expression levels further indicate differences in the pathophysiological role of CD14 and CD14-mediated lipopolysaccharides signal transduction with regard to the stage as well as the type of the underlying liver disease.

Genetic determinants of alcoholic liver disease

“…This association was confirmed in a second smaller study which also showed that CD14 -159TT homozygotes have higher levels of the LPS-binding acute phase proteins LBP and soluble CD14 than carriers of the C allele 57. A third study also found a higher frequency of the CD14 -159TT in subjects with alcoholic cirrhosis compared with those without, but the sample size was relatively low with only 62 cases (118 controls) 58. Finally, a small genetic study from Portugal could not find an association between carriage of the CD14 -159T allele and ALD 59…”

Host Response to Translocated Microbial Products Predicts Outcomes of Patients With HBV or HCV Infection

“…Higher sCD14 levels may reflect more cells responding to LPS or a genetic predisposition towards increased LPS responsiveness. Indeed, high sCD14 levels in the setting of alcohol abuse 42 or HCV infection HCV infection 43 have been associated with a polymorphism in the promoter region of the CD14 gene (−159C/T). LPS-induced monocyte activation may increase systemic cytokine production, particularly as both circulating CD14 + CD16 + monocytes and hepatic macrophages are increased in cirrhosis 44 .…”

Soluble CD14: Role in atopic disease and recurrent infections, including otitis media

“…Soluble CD14 has been associated with a variety of diseases, such as meningococcal sepsis [23] (and with severity of sepsis [33]), human immune deficiency [4], acute pancreatitis [34], recurrent middle-ear infections [31], chronic liver disease [35], Gaucher type 1 disease [36], systemic lupus erythematosus [37], and diabetes mellitus type 1 and possibly type 2 [38].…”