**7.2 With or without 'hyperferritinemia and iron overloading, related with T2DM'**

A strong correlation between iron overload and several manifestations of the metabolic syndrome including NAFLD and T2DM has been demonstrated recently. It has clashed that increased ferritin levels observed in most patients with NASH are due to the underlying necro-inflammatory condition, which assists the release of tissue iron and ferritin into the blood [103].

The corelation between NASH and IR has recently been weaved as a 'new iron overload syndrome' characterised by hyperferritinemia. The dysmetabolic iron overload syndrome has now been established as a frequent finding in the general population, occurring in about one-third of patients with NAFLD and metabolic syndrome. Altered regulation of iron transport genetic factors is considered to be the main contributor to iron overload [26]. The exact mechanisms underlying the deposition of hepatic iron remain unknown and unsettled. One of the clinical factors associated with steatosis, IR and subclinical inflammation, often in the presence of predisposing features of NASH, is the build-up of iron in the liver accompanied by increased levels of serum ferritin, which is highly suggestive of the central role of iron in disease progression [104].

Iron is known to generate highly reactive hydroxyl radicals through the Fenton reaction, and the resultant ROS may contribute to liver damage. Significant increases in hepatic 8-OHdG generated by OH radicals have been reported in patients with NASH, particularly in correlation with iron overload, IR and severity of hepatic steatosis [26]. The mechanisms involved in iron accumulation in NAFLD, and in inducing IR, metabolic, hepatic and vascular damage by iron accumulation are not yet well understood and should be further investigated [92].

The association between hyperferritinemia, insulin resistance and T2DM has been discussed among hepatologists, diabetologists and endocrinologists recently. There is an increased prevalence of T2DM associated with two common iron overload conditions, HFE hereditary hemochromatosis (HH) and β-thalassemia major [28]. The persistence of the association between serum ferritin concentration and T2DM after correction for hsCRP implies that inflammation alone does not entirely explain the association between hyperferritinemia and diabetes.

Bugianesi et al. [43] found that the serum ferritin concentration is not associated with hepatic iron concentration in NAFLD but is a marker of severe histologic damage in 2004. In the large NASH Clinical Research Network (CRN) cohort of 628 patients, Kowdley et al. [105] demonstrated that a serum ferritin concentration greater than 1.5 times the upper limit of normal was independently associated with advanced fibrosis and increased NAFLD activity score. However, other studies have not found such a clear association [39, 106].

Notably, in an Italian cohort of 587 patients with NAFLD, Valenti et al. [26] showed that serum ferritin concentration did not predict fibrosis stage >1. As would be expected, the serum ferritin concentration was higher in the patients who had hepatic iron staining than those who did not, but those with non-parenchymal iron had much higher ferritin values (606 μg/L) than those with hepatocellular iron (serum ferritin 354 μg/L) P < 0.0001. This suggests that macrophage iron can cause hyperferritinemia either by direct release of ferritin or cytokine-mediated stimulation of ferritin released by other cells.
