*Regulation of Iron Metabolism in NAFLD/NASH DOI: http://dx.doi.org/10.5772/intechopen.107221*

oxidative stress as well as hepatic iron concentrations and hepatocyte damage in chronic liver disease [45]. Elevated serum ferritin in NASH may be caused by ironunrelated oxidative stress, such as that derived from FFA, lipid peroxide, cytokines and induction of cytochrome P450 enzymes (CYP2E1 and CYP4AC-) [46]. Thus, the role of hepatic iron in the pathogenesis of NASH or abnormal iron indices in NASH remains debatable and unsettled.

Under usual conditions, intracellular protection from iron-induced oxidative stress is facilitated by sequestration of iron within ferritin [47]. Pathologic states of iron overload often led to saturation of the serum iron transporter, transferrin, which increases the serum levels of toxic non-transferrin bound iron (NTBI). NTBI is readily absorbed by tissues such as the liver and cardiac muscle [48]. The association between hyperferritinemia, insulin resistance and T2DM is compelling. The odds ratios for developing diabetes in those with elevated serum ferritin levels were high at 3.61 for women and 4.94 for men [49–51]. The connotation between hyperferritinemia and histologic markers of liver injury in NAFLD is reasonably firm. In 2004, Bugianesi et al. [43] showed that serum ferritin concentration is not associated with hepatic iron concentration in NAFLD, but is a marker of severe histologic damage.

In an earlier study by Chitturi et al. [44] of 93 patients with NASH, 33% of whom had advanced fibrosis, the authors found that serum ferritin concentration was not an independent predictor of advanced fibrosis. This implies that the ferritin association with NAFLD is not simply a result of NAFLD itself causing hyperferritinemia. Moreover, the results suggest that the link between hyperferritinemia and NAFLD could be explained by insulin resistance. It also appears that it has a direct role in the activation of hepatic macrophages and HSCs. In humans with NAFLD, reticuloendothelial iron has been shown to be associated with apoptosis, indicated by increased serum cytokeratin-18 (CK-18) fragments and increased hepatic TUNEL staining of liver sections [52]. Iron may also contribute to liver injury in NAFLD by generating endoplasmic reticulum stress [53]. Additionally, hepatic iron loading in mice upregulates cholesterol biosynthesis pathways; this has been proposed as an additional mechanism of iron-induced liver injury in NASH [54].
