Evaluation of noninvasive markers for the diagnosis of cystic fibrosis liver disease.

OBJECTIVES: In cystic fibrosis (CF), liver disease (LD) is the third leading cause of mortality. As liver biopsy was considered inconsistent in CFLD diagnosis, a combination of modalities were utilized in the conventional Debray criteria (DC). More recently, noninvasive liver fibrosis biomarkers were applied by Koh et al (New criteria-NC). In the current study, we aimed to evaluate noninvasive biomarkers for the CFLD diagnosis. METHODS: Longitudinal data were collected from a cohort of genetically confirmed CF patients. CFLD was diagnosed by both DC and NC. Apart from transient elastography (TE) > 6.8 kPa, biomarkers incorporated in the NC included AST/ALT-ratio (AAR) ≥ 1, FIB-4 index ≥3.25 and APRI >0.50. RESULTS: 62 patients with CF, [56.5% male, age at enrollment 25 (22-31) years], were prospectively followed-up for 33 (28-36) months. Sixteen (25.8%) and 27 (43.5%) patients met DC and NC, respectively. Twenty-four fulfilling NC had at least one positive biomarker (6 TE, 7 AAR, 6 both TE and AAR, 2 both APRI and AAR and 3 both APRI and TE). Thirteen (48.1%) had diffuse LD/cirrhosis by the NC and all had at least one additional parameter classifying them as CFLD. From the 14 (51.8%) with no-diffuse-LD, 64.3%, 14.3% and 21.4% had 2, 3 and 4 of the necessary modalities incorporated in NC, respectively, confirming their classification as CFLD. TE was 100% specific to rule in CFLD but had a moderate sensitivity. CONCLUSIONS: NC were able to identify 17.7% more CFLD patients compared to DC. The multiple biomarkers incorporated in NC may enhance the ability to detect CFLD.

Interactions between CYP1A1 polymorphisms and exposure to environmental tobacco smoke in the modulation of lymphocyte bulky DNA adducts and chromosomal aberrations.

CYP1A1 plays an important role in the metabolic activation of polycyclic aromatic hydrocarbons (PAH), carcinogenic components of air pollution. The influence of CYP1A1 genotype (*2A, *2B and *4) on the levels of lymphocyte bulky DNA adducts and the frequency of cells with aberrant chromosomes was assessed in 194 non-smoking subjects in whom recent exposure to environmental tobacco smoke (ETS) and airborne particulate-associated PAH were measured during two consecutive seasons (winter and summer). While CYP1A1*4 had no consistent effect on either biomarker of genetic damage, the levels of both biomarkers responded in a parallel fashion to changes in exposure/CYP1A1*2A genotype combinations during both seasons. Specifically, the levels of both biomarkers were increased in carriers of at least one CYP1A1*2A allele, as compared with CYP1A1*1 homozygotes, in subjects with ETS exposures >0.8 h/day during the previous 4 days and mean personal exposure to benzo[a]pyrene <0.9 ng/m3 during the previous 24 h (all P < 0.05). Outside these exposure limits the differential effect in CYP1A1*2A variants was lost. Although the numbers of subjects with the CYP1A1*2B polymorphism was small, the same trend appeared to be followed in this case. These effects are interpreted as resulting from differential induction of CYP1A1 expression in CYP1A1*2A and CYP1A1*2A/*2B carriers by components of ETS-polluted air at levels of exposure readily suffered by large segments of the general population and suggest that subjects with these genotypes may have increased susceptibility to the genotoxic effects of ETS.