The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled trial.

UNLABELLED: Iron is implicated in the pathogenesis of liver injury and insulin resistance (IR) and thus phlebotomy has been proposed as a treatment for nonalcoholic fatty liver disease (NAFLD). We performed a prospective 6-month randomized, controlled trial examining the impact of phlebotomy on the background of lifestyle advice in patients with NAFLD. Primary endpoints were hepatic steatosis (HS; quantified by magnetic resonance imaging) and liver injury (determined by alanine aminotransaminase [ALT] and cytokeratin-18 [CK-18]). Secondary endpoints included insulin resistance measured by the insulin sensitivity index (ISI) and homeostasis model of assessment (HOMA), and systemic lipid peroxidation determined by plasma F2-isoprostane levels. A total of 74 subjects were randomized (33 phlebotomy and 41 control). The phlebotomy group underwent a median (range) of 7 (1-19) venesection sessions and had a significantly greater reduction in ferritin levels over 6 months, compared to controls (-148 ± 114 vs. -38 ± 89 ng/mL; P < 0.001). At 6 months, there was no difference between phlebotomy and control groups in HS (17.7% vs. 15.5%; P = 0.4), serum ALT (36 vs. 46 IU/L; P = 0.4), or CK-18 levels (175 vs. 196 U/L; P = 0.9). Similarly, there was no difference in end-of-study ISI (2.5 vs. 2.7; P = 0.9), HOMA (3.2 vs. 3.2; P = 0.6), or F2-isoprostane levels (1,332 vs. 1,190 pmmol/L; P = 0.6) between phlebotomy and control groups. No differences in any endpoint were noted in patients with hyperferritinemia at baseline. Among patients undergoing phlebotomy, there was no correlation between number of phlebotomy sessions and change in HS, liver injury, or IR from baseline to end of study. CONCLUSION: Reduction in ferritin by phlebotomy does not improve liver enzymes, hepatic fat, or IR in subjects with NAFLD.

Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Significant hepatic fibrosis is prognostic of liver morbidity and mortality in non-alcoholic fatty liver disease (NAFLD); however, it remains unclear whether non-invasive fibrosis models can determine this end-point. We therefore compared the accuracy of simple bedside versus complex fibrosis models across a range of fibrosis in a multi-centre NAFLD cohort. METHODS: Simple (APRI, BARD) and complex (Hepascore, Fibrotest, FIB4) fibrosis models were calculated in 242 NAFLD subjects undergoing liver biopsy. Significant (F2-4) and advanced fibrosis (F3,4) were defined using Kleiner criteria. Models were compared using area under the receiver operator characteristic curves (AUC). Cut-offs were determined by Youden Index or 90% predictive values. RESULTS: For significant fibrosis, non-invasive fibrosis models had modest accuracy (AUC 0.707-0.743) with BARD being least accurate (AUC 0.609, P < 0.05 vs others). Using single cut-offs, sensitivities and predictive values were < 80%; using two cut-offs, > 75% of subjects fell within indeterminate ranges. Simple models had significantly more subjects within indeterminate ranges than complex models (99.1-100% vs 82.1-84.4% respectively, P < 0.05 for all). For advanced fibrosis, complex models were more accurate than BARD (AUC 0.802-0.858 vs 0.701, P < 0.05). Using two cut-offs, complex models had fewer individuals within indeterminate ranges than BARD (11.1-32.3% vs 70.7%, P < 0.01 for all). For cirrhosis, complex models had higher AUC values than simple models. CONCLUSIONS: In NAFLD subjects, non-invasive models have modest accuracy for determining significant fibrosis and have predictive values less than 90% in the majority of subjects. Complex models are more accurate than simple bedside models across a range of fibrosis.