Reply to: “IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients”
Authors: Salvatore Petta, Antonio Craxi
Journal: Journal of Hepatology (2012)

IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver diseaseJournal of HepatologyVol. 56Issue 6PreviewGenetic background may affect liver damage in patients with non-alcoholic fatty liver disease (NAFLD). The main outcomes of the study were to assess whether IL28B rs12979860 and rs8099917 polymorphisms, together with PNPLA3 rs738409 C>G polymorphism, are associated with lobular inflammation and fibrosis, in NAFLD patients. Full-Text PDF We recently reported a link between interleukin 28B (IL28B) rs12979860 genotype and severity of liver disease, in a cohort of 160 biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients, forty percent of them with obesity, and with a mean age of 45.6 years [[1]Petta S. Grimaudo S. Cammà C. Cabibi D. Di Marco V. Licata G. et al.IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease.J Hepatol. 2012; 56: 1356-1362Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. In particular, we observed that the IL28B CC genotype, associated in chronic hepatitis C (CHC) with a higher rate of sustained virological response after antiviral therapy [[2]Ge D. Fellay J. Thompson A.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3137) Google Scholar], in NAFLD patients was independently associated with a higher prevalence of moderate-severe liver lobular inflammation and fibrosis [[1]Petta S. Grimaudo S. Cammà C. Cabibi D. Di Marco V. Licata G. et al.IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease.J Hepatol. 2012; 56: 1356-1362Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. Our results were in line with other data on CHC patients suggesting a link, even if not confirmed in other studies, between IL28B CC genotype and severity of liver disease [3Abe H. Ochi H. Maekawa T. Hayes C.N. Tsuge M. Miki D. et al.Common variation of IL28 affects gamma-GTP levels and inflammation of the liver in chronically infected hepatitis C virus patients.J Hepatol. 2010; 53: 439-443Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 4Marabita F. Aghemo A. De Nicola S. Rumi M.G. Cheroni C. Scavelli R. et al.Genetic variation in IL28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection.Hepatology. 2011; 54: 1127-1134Crossref PubMed Scopus (38) Google Scholar]. In this complex picture, we read with great interest data reported by Garrett and colleagues [[5]Garrett M.E. Abdelmalek M. Ashley-Koch A. Hauser M.A. Moylan C.A. Pang H. et al.IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients.Hepatology. 2011; 54: 1127-1134Crossref PubMed Scopus (115) Google Scholar] on the association between IL28B genotype and severity of histological features in NAFLD patients. Specifically, the authors did not identify any association among IL28B status and steatosis, inflammation, ballooning and fibrosis in their cohort of NAFLD patients [[5]Garrett M.E. Abdelmalek M. Ashley-Koch A. Hauser M.A. Moylan C.A. Pang H. et al.IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients.Hepatology. 2011; 54: 1127-1134Crossref PubMed Scopus (115) Google Scholar]. However, as correctly highlighted by the same authors, they enrolled a cohort of severe obese NAFLD patients evaluated for bariatric surgery [[5]Garrett M.E. Abdelmalek M. Ashley-Koch A. Hauser M.A. Moylan C.A. Pang H. et al.IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients.Hepatology. 2011; 54: 1127-1134Crossref PubMed Scopus (115) Google Scholar], and therefore very different from our enrolled cohort [[1]Petta S. Grimaudo S. Cammà C. Cabibi D. Di Marco V. Licata G. et al.IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease.J Hepatol. 2012; 56: 1356-1362Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. In particular, it should be possible to assume that the genetic background probably discriminating the "normal" from to the "morbidly obese" NAFLD patient, could per se explain the different results observed. In other words, it is plausible to state that "morbidly obese NAFLD" is a disease different from "normal NAFLD". Beyond these considerations, the results by Garret and colleagues [[5]Garrett M.E. Abdelmalek M. Ashley-Koch A. Hauser M.A. Moylan C.A. Pang H. et al.IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients.Hepatology. 2011; 54: 1127-1134Crossref PubMed Scopus (115) Google Scholar] could suggest an obesity-dependent effect of the IL28B genotype on liver damage in NAFLD patients. Accordingly, we analyzed separately non-obese (n = 94) and obese (n = 66) NAFLD patients, observing that the association between IL28B genotype and severity of liver damage was maintained only in non-obese NAFLD patients. In particular, among obese patients, a moderate-severe liver lobular inflammation was observed in 17/28 IL28B CC, compared to 16/38 IL28B TT/TC NAFLD patients (p= 0.13). By contrast, the prevalence of moderate-severe lobular inflammation was significantly higher in non-obese IL28B CC, compared to non-obese IL28B TT/TC NAFLD patients (28/46 vs. 9/48; p<0.001). The protective role of IL28B TT/TC genotype against moderate-severe lobular inflammation was maintained at multivariate logistic analysis (OR 0.171, 95% C.I. 0.058–0.507, p= 0.001). As observed with lobular inflammation, the association between liver fibrosis and IL28B genotype was present only in non-obese patients. Specifically, in obese NAFLD patients, the prevalence of F2-F4 liver fibrosis was not significantly different between IL28B CC and IL28B TT/TC patients (17/28 vs. 22/38; p= 0.81). By contrast, the prevalence of F2-F4 was significantly higher in non-obese IL28B CC, compared to non-obese IL28B TT/TC NAFLD patients (25/46 vs. 14/48; p= 0.01). These data overall seem to suggest an effect of IL28B CC genotype only in patients at lower metabolic risk, and not in obese patients, were the impact of metabolic alterations on NAFLD severity probably overcomes the pathogenic role of genetic background. However, due to small sample of obese patients in our cohort, a further validation is needed. Finally, the lack of association between IL28B genotype and severity of steatosis in our NAFLD group, which was instead observed in CHC patients (protective role of IL28B C/C against steatosis) [[6]Tillmann H.L. Patel K. Muir A.J. Guy C.D. Li J.H. Lao X.Q. et al.Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C.J Hepatol. 2011; 55: 1195-1200Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar] is not surprising. In fact, first, we evaluated a population where all patients have steatosis, mostly moderate-severe, and second, differently from NAFLD patients, it is plausible to suppose a strong interaction among HCV, IL28B genotype and metabolic factors in the genesis of steatosis in CHC. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.