Journal of Hepatology
Volume 46, Issue 4 , Pages 549-552, April 2007

Ferritin, metabolic syndrome and NAFLD: Elective attractions and dangerous liaisons

Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Centre for Diagnosis and Therapy of Hemochromatosis, San Gerardo Hospital, Via Pergolesi 33, 20052 Monza, Italy

published online 26 January 2007.

Article Outline

 

Accumulating evidence suggests a link between serum ferritin, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). Several studies showed high ferritin levels and/or increased prevalence of hyperferritinemia in patients with the whole metabolic syndrome [1], [2] or its single components [3], [4], [5], [6], with serum ferritin showing a linear increase with the increasing number of metabolic syndrome features [1]. Epidemiologic studies have further supported this notion by suggesting that serum ferritin could be a marker of insulin resistance [7]. Fat accumulation in the liver seems to be a very early event in the course of insulin resistance and several studies demonstrated the strong association between NAFLD, insulin resistance and metabolic syndrome features [8], [9], [10], [11]. Serum ferritin is indeed frequently increased in NAFLD patients [12], [13], [14], [15] and related to disease progression [15]. Finally, a common hepatic iron overload condition, characterised by hyperferritinemia with normal or slightly increased transferrin saturation, was described in non-C282Y homozygotes and named insulin-resistance hepatic iron overload [IR-HIO] syndrome due to frequent association with hepatic steatosis and metabolic abnormalities [16].

Despite the substantial amount in support of an association between ferritin, iron overload, insulin resistance, and NAFLD the mechanisms underlying this intricate and intriguing relation are still unclear. Zelber-Sagi et al. in this issue of the Journal [17] tried to fill one of these gaps. They showed that NAFLD was responsible for the association between serum ferritin and the metabolic syndrome and most of its components suggesting that the relation between serum ferritin and most of metabolic syndrome features might be mediated by the presence of NAFLD at population-based level. Expanding their conclusions, they also suggest that the association found in previous studies between ferritin and components of the metabolic syndrome may depend from undiagnosed NAFLD. Among metabolic features, insulin appeared to be the strongest predictor of increased serum ferritin levels, but the association between serum ferritin and insulin was much more evident in the NAFLD group. Accordingly, the interaction between NAFLD and hyperinsulinemia was the major determinant of serum ferritin levels in a linear multivariate analysis, besides gender.

Despite the novelty of information, the cross-sectional design of the study prevents one from making inferences about the directionality of these associations. Two prospective studies provided evidence that increased ferritin levels precede the development of diabetes [18], [19]. However, it remains unanswered whether serum ferritin is a marker of insulin resistance or whether elevated serum ferritin may contribute, via iron accumulation, to the pathogenesis of altered metabolic states.

An inherent problem in the study of this issue lies in the relation between serum ferritin and iron stores in patients with metabolic syndrome and NAFLD. Iron excess can induce hepatic damage and glucose intolerance or diabetes in hemochromatosis and thalassemia patients [20], [21], [22]. However, they represent severe iron overload conditions that can be hardly taken as models for disorders such as NAFLD and metabolic syndrome where liver iron stores are often normal or only slightly increased. In addition, recent data do not support insulin resistance as being a primary consequence of iron overload in hemochromatosis [22]. On the other side, serum ferritin has several limitations as index of body iron stores and most aspects of its secretion remain unknown [23]. Ferritin enters the circulation via a specific secretory pathway from its source tissues or is released from damaged cells [24], [25]. In normal subjects secreted ferritin makes a major contribution to the serum ferritin pool, but in patients with chronic liver diseases high serum ferritin concentrations may reflect an increased release of tissue ferritin from injured hepatocytes into the circulation. Second, ferritin biosynthesis is stimulated at the transcriptional and translational levels by several factors other than iron. Cytokine-dependent control is particularly relevant to inflammation, because ferritin is an acute phase reactant and several pro-inflammatory cytokines stimulate ferritin synthesis [24], [25]. Both hepatocellular necrosis and inflammation can occur in NAFLD and may lead to disproportionate serum ferritin levels. Indeed, almost all of the few studies that analysed both serum and tissue iron indices in patients with NAFLD or metabolic syndrome features showed that increased transferrin saturation and hepatic iron were far less common than hyperferritinemia (Table 1) [12], [13], [14], [15]. Moreover, serum ferritin and insulin resistance but not iron stores were significant predictors of severe fibrosis in NAFLD patients [15]. Thus, it was suggested that high ferritin levels in NAFLD patients are more likely the expression of their metabolic state and/or hepatic damage [13], [15] and that increase of serum ferritin levels can be induced either by the cause (insulin resistance) or the consequence (hepatocellular damage) of NAFLD, as also suggested by the present findings by Zelber-Sagi et al. [17]. The known relationship between subclinical inflammation and metabolic syndrome does not seem to play a major role in determining serum ferritin concentrations in NAFLD or metabolic syndrome since CRP did not correlate with serum ferritin in the general population [3], [6], [17] and in patients with the metabolic syndrome [1], [2]. However, more subtle inflammatory conditions, maybe at the local level in the liver or adipose tissue, cannot be excluded. Indeed, CRP expression is increased in liver and in adipose tissue of obese patients [26], adipose tissue contributes to the production of pro-inflammatory molecules, and the increase in their production participates in the metabolic syndrome [27]. In addition, it has been recently shown that adipose tissue expresses hepcidin, a key regulator of iron homeostasis, and that this expression is enhanced in massively obese patients and correlates with adipose tissue expression of CRP and interleukin-6 (IL-6) [28]. This finding is intriguing if we consider that hepcidin decreases iron absorption and reduces iron mobilization from stores leading to decreased serum iron and hyperferritinemia [29]. However, it should be taken with caution since the relative contribution of adipose tissue in circulating hepcidin is difficult to estimate, and all these findings seem to be more related to adiposity (through increased adipocyte IL-6 secretion) than to insulin resistance and NAFLD [26], [28].

Table 1. Number (%) of patients with NAFLD showing increased serum and hepatic iron indices
Author (ref.)PtsSerum iron indices reference valuePts with increased serum iron indicesHepatic iron indices reference valuePts with increased hepatic iron stores
n TS n (%)SF n (%) n (%)
George [12]51TS>55%SF>300μg/l9/41 (22)26/42 (62)Perls’ stain>121 (41)
HIC>40μmol/g10/47 (21)
Fargion [13]90TS>45%SF>320μg/l1 (1)24 (27)Perls’ stain>13/20 (15)
Chitturi [14]93TS>55%SF>300μg/l5 (6)37 (40)Perls’ stain>19 (10)
Bugianesi [15]263TS>55%SF>350μg/l19 (7)55 (21)HIC>27μmol/g7/80 (9)

Only studies including both measures are reported.

It can be argued that if ferritin, NAFLD and metabolic syndrome are linked together they should be modified in parallel by manoeuvres that affect either features. Phlebotomy-induced iron depletion improved insulin sensitivity in patients with NAFLD [30], [31], some metabolic features in IR-HIO patients [32] and serum ALT in both [30], [31], [32]. These findings could even occur in the absence of increased iron stores [30], [33] suggesting that iron may exert its influence at a very subtle molecular level and that iron depletion may decrease hepatocellular injury and ALT activity either enhancing insulin sensitivity [34] or reducing iron-mediated oxidative stress [35], [36]. Moderate weight loss by diet and exercise is effective in reducing insulin resistance and is the first line therapy for NAFLD [37], but its effect on serum ferritin level is controversial [13], [32], [38], [39]. Nevertheless, there is evidence that the diet-related decrease of serum ferritin depends on the relative proportion of the two components (iron overload and metabolic derangements) that influence ferritin changes in these patients. Further insights derive from IR-HIO patients. As compared to hemochromatosis patients with equal amounts of hepatic iron concentration (HIC) and iron removed, their serum ferritin concentrations are three times higher [39]. Although this finding might simply suggest that serum ferritin overestimates the true amount of hepatic iron in IR-HIO, another explanation must be considered. Previous studies showed that relatively little ferritin is released from liver parenchymal cells in early hemochromatosis [40] and that this may be because serum ferritin largely originates from cells of the reticuloendothelial system that are generally spared by iron accumulation in the early stage of disease. Accordingly, hyperferritinemia was more correlated with the mesenchymal than hepatocellular iron score in hemochromatosis [41]. Thus, not only the total amount of hepatic iron, but also the relative distribution between different cellular compartments might be important in determining serum ferritin levels. This is not trivial if we consider that in IR-HIO hepatic iron deposition shows a particular distribution with large involvement of the sinusoidal compartment [42] that can be undervalued by HIC and SQUID measurement and by Scheuer’s parenchymal iron grading.

In Fig. 1 we try to summarize the links among ferritin (and iron), metabolic syndrome and NAFLD. Only a proportion of subjects with metabolic alterations appear at risk for iron overload [1], [4] suggesting that other factors are involved. These patients have the IR-HIO. On the other side only a proportion of IR-HIO patients had features that suggest the presence of the metabolic syndrome [16]. It is not known whether metabolic alterations may lead to iron overload in susceptible individuals or iron accumulation precedes metabolic syndrome and NAFLD in IR-HIO. More accurate measurement of the amount and distribution of hepatic iron and a definition of IR-HIO according to the recent metabolic syndrome criteria [43] are needed to clarify these relations. It is also needed to understand if and when the elective attraction among ferritin, metabolic syndrome and NAFLD turns into a dangerous iron-mediated liaison favouring hepatic damage. Studies on iron-related genes expression and genetic polymorphisms may help to clarify the alteration of iron homeostasis associated with metabolic syndrome and IR-HIO and to verify whether a genetic predisposition to iron overload exists in these patients.

  • View full-size image.
  • Fig. 1. 

    Relationship among metabolic syndrome, serum ferritin, NAFLD, and hepatic iron overload. Only a proportion of patients with the metabolic syndrome has IR-HIO and vice versa. Insulin resistance may induce hyperferritinemia either directly or indirectly through NAFLD-related hepatic damage; local inflammatory changes may also activate macrophage retention of iron by hepcidin-mediated regulation and further stimulate ferritin secretion. In this condition the cascade of events related to insulin resistance, fatty acid accumulation, and oxidation are the major determinants of serum ferritin. Hepatic iron may be fairly normal, but iron retained within activated mesenchymal cells might contribute to the generation of reactive oxygen species and hepatic damage. Hepatic damage, by releasing cellular iron and tissue ferritin, may favour macrophage iron accumulation and hyperferritinemia. IR-HIO may represent the other end of the spectrum. The biochemical and histological iron patterns of this syndrome resemble those observed in the ferroportin disease [44] suggesting that an impaired cellular iron release might be involved in the pathogenesis of this form of iron overload.

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PII: S0168-8278(07)00040-2

doi:10.1016/j.jhep.2007.01.004

Journal of Hepatology
Volume 46, Issue 4 , Pages 549-552, April 2007

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