Serum Ceruloplasmin, Ferritin, and Their Ratio Are Significantly Associated With Nonalcoholic Steatohepatitis in Patients With NAFLD

Abstract

Introduction: Nonalcoholic fatty liver disease (NAFLD) has a histologic spectrum that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), to eventually advanced fibrosis and cirrhosis. Oxidative stress (OS) plays a central role in the pathogenesis and progression of NAFLD, and changes in proteins associated with metal homeostasis may exacerbate OS. We aimed to investigate the correlation of serum ceruloplasmin (antioxidant), ferritin (OS marker), and their ratio with NAFLD and its progression to NASH. Methods: The study population consisted of 123 adult patients who underwent a liver biopsy for clinically suspected NAFLD. We collected serum levels of ceruloplasmin, ferritin, iron, and transferrin saturation and we calculated the ceruloplasmin to ferritin ratio (ceruloplasmin/ ferritin). The main histologic features of NASH were scored by an experienced pathologist including steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2). Fibrosis was staged (0 - 4). Logistic regression analysis was performed to study the association of ceruloplasmin, ferritin, and their ratio with NASH. Results: The mean age was 48.9±12.0 years old. 47.2% were female. Fifty-two percent had biopsy-proven NASH, whereas 51% had fibrosis (stage 1 in 22.8%, stage 2 in 12.2%, stage 3 in 12.2%, and stage 4 in 4.1%). Among patients with NASH, mean ceruloplasmin was significantly lower (P=0.004) and mean ferritin was significantly higher (P=0.001) compared with those without NASH (Figure 1). Similarly, ceruloplasmin was significantly lower (P=0.049) and ferritin was higher (P=0.001) in patients with fibrosis (F1-4) compared to no fibrosis (F0). After adjusting for multiple confounders, the likelihood of having NASH decreased by 23% for every 5-unit increase in ceruloplasmin [Odds ratio (OR) 0.77 (0.62, 0.95); p=0.017], increased by 10% for every 25-unit increase in ferritin [OR 1.1 (1.05, 1.2); p=0.001], and decreased by 75% for every 0.5-unit increase in the ceruloplasmin/ferritin ratio [OR 0.25 (0.09, 0.69); p= 0.007]. There was a significant association between ceruloplasmin, ferritin, and their ratio with the grade of steatosis, inflammation, ballooning, and the NAFLD activity score (p<0.05 for all).Figure 1: The association of ceruloplasmin, ferritin, and ceruloplasmin-ferritin ratio with NASH.Conclusion: Lower levels of ceruloplasmin and higher levels of ferritin are significantly associated with NASH. Ceruloplasmin/ferritin ratio should be further investigated as a noninvasive predictor of the presence of NASH and the severity of NAFLD.