Dysmetabolic Iron Overload Syndrome: History
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Contributor:
Sandra Maria Barbalho
,
Lucas Fornari Laurindo
,
Ricardo José Tofano
,
Uri Adrian Prync Flato
,
Claudemir G. Mendes
,
Ricardo de Alvares Goulart
,
Ana Maria Gonçalves Milla Briguezi
,
Marcelo Dib Bechara

Dysmetabolic iron overload syndrome (DIOS) corresponds to the increase in iron stores associated with components of metabolic syndrome (MtS) and in the absence of an identifiable cause of iron excess. DIOS is usually asymptomatic and can be diagnosed by investigating MtS and steatosis. About 50% of the patients present altered hepatic biochemical tests (increased levels of γ-glutamyl transpeptidase itself or associated with increased levels of alanine aminotransferase). The liver may present parenchymal and mesenchymal iron overload, but the excess of iron is commonly mild. Steatosis or steatohepatitis is observed in half of the patients. Fibrosis is observed in about 15% of patients. Hyperferritinemia may damage the myocardium, liver, and several other tissues, increasing morbidity and mortality.

  • dysmetabolic iron overload syndrome
  • metabolic syndrome
  • hyperferritinemia

1. Introduction

Cardiovascular diseases (CVD) are responsible for most causes of death worldwide and are strongly associated with metabolic syndrome (MtS), which comprises risk factors related to high morbidity. The primary underlying mechanism related to the onset and maintenance of CVD is atherosclerosis [1][2][3][4][5][6].
In addition to MtS, researchers have described the occurrence of another condition, the dysmetabolic iron overload syndrome (DIOS) corresponds to the increase in the body iron stores, associated with components of MtS, and in the absence of identifiable cause of iron excess [7][8][9][10][11][12][13]. Most DIOS patients also possess nonalcoholic fatty liver disease (NAFLD), a condition that is best defined as metabolic associated fat liver disease (MAFLD) [14]. Although MAFLD, which is also a result of insulin resistance and MtS, is usually but not invariably followed by expanded body iron stores, iron depletion can attenuate steatosis in MAFLD [10][15][16][17]. The histological patterns found in DIOS associates both mesenchymal and parenchymal areas. The iron deposition on the hepatic reticuloendothelial system cells is implicated with increased hepatic apoptosis in MAFLD patients, additionally to higher percentages of advanced hepatic fibrosis, higher portal inflammation, and augmented hepatocellular ballooning [18][19][20][21][22][23]. 
Iron is a fundamental element for the maintenance of homeostasis. It is essential to electron transport, oxygen transport, DNA synthesis, and several other actions, but it may also be toxic. Disruption in iron metabolism as observed in patients with DIOS may be multifactorial. Diets rich in iron associated with genetic factors may trigger the overload condition, related to crosstalk observed between liver and visceral adipose tissue. Macrophages seem to be especially important in the homeostasis of systemic iron levels, and ferroportin is the iron exporter and plays a role in mediating the exit of iron from macrophages to circulation [24][25][26][27].
DIOS is closely related to oxidative stress (OS), and this condition is closely associated with several pathological conditions such as inflammatory diseases, hypertension, diabetes, heart failure, and cancer [28][29][30][31].
The presence of MtS factors, hyperferritinemia, and altered transferrin saturation are disorders that represent a serious global problem. Both MAFLD and its aggressive form, nonalcoholic steatohepatitis (NASH), are linked with higher morbidity and mortality. The incidence of NASH is estimated to increase by more than 50% in the next ten years. Moreover, MAFLD incidence nowadays may vary from up to one-quarter of the world population and may be higher than 60% in diabetic patients and about 90% in patients who underwent bariatric surgery [10][32][33][34][35][36][37][38].

2. Ferritin and Hyperferritinemia

Iron is a crucial element for all living systems, essential for oxygen transport in hemoglobin and cellular energy production and serving as a cofactor or catalyst in several enzymatic processes. The iron-containing protein ferritin reflects the homeostasis of human iron storage and iron delivery, which is crucial for the maintenance of the anteriorly mentioned biological processes [39][40][41][42]. 
Hyperferritinemia is a condition where excessively high levels of ferritin are observed, indirectly indicating iron overload, which damages the myocardium, the liver, and several other tissues, increasing morbidity and mortality. Nevertheless, more than 90% of hyperferritinemia cases are derived from four major causes: inflammatory conditions, cytolysis, alcoholism, and MtS. Another critical cause that should be seen separately is genetic hemochromatosis. The differentiation of these conditions can be performed with laboratory tests such as hemogram, transferrin saturation, liver function tests, creatinine phosphokinase (CPK), C reactive protein, glycemia, total cholesterol, and triglycerides. Immune and autoimmune affections can also possibly cause hyperferritinemia [39][43][44][45][46][47].
Ferritin seems to play an essential role in angiogenesis, cells proliferation, and immunosuppression. Additionally, it can also be considered as an inflammatory acute-phase protein. Some studies suggested an association between high ferritin levels and chronic diseases, such as CVD and cancer. In CVD, ferritin can lead to a dual pro-inflammatory effect because high levels can represent an acute phase similar to C reactive protein. Low levels can also precipitate inflammation and, thus, increase the pro-inflammatory cytokines. These conditions can be related to CVD progression [39][44][48][49][50]. Hyperferritinemia has also been associated with NAFLD/MAFLD and with polycystic ovary syndrome [8][16][51][52].

3. Hepcidin

Hepcidin is a peptide hormone released by liver hepatocytes involved in regulating ferroportin expression, which is the major iron export protein presented in cells. Hepcidin can bind to ferroportin, leading to its internalization and degradation, which only reduces iron export from different vias. This process inhibits cellular iron exportation from macrophages. Hepcidin also inhibits iron uptake in the gut that, together with inhibition of recycling iron from macrophages, decreases iron levels in plasma. The axis hepcidin-ferroportin has a central regulatory role in iron homeostasis. In hereditary hemochromatosis, both the expression and function of hepcidin are disturbed and lead to increase in ferroportin due to the low circulating hepcidin levels resulting in augmentation of iron absorption in the gut and pathological deposition of this element in tissues [29][53][54][55][56].
Stimulation of hepcidin in the liver reduces ferroportin levels, resulting in the inhibition of cellular iron mobilization to the plasma. Acute inflammatory and infectious conditions may also increase hepcidin expression. Induction of hepcidin resulting from inflammatory processes possibly interferes with iron metabolism in acute or chronic inflammation disorders. In case of infections, hepcidin induction is associated with sequestration of intracellular iron, depriving microorganisms of this important factor. In chronic inflammation, hepcidin expression is increased principally due to interleukin 6 (IL-6) and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) expressions [55][57][58].
A disrupted low synthesis of hepcidin has been associated with NAFLD and could help the iron uptake and increase predisposition for DIOS. Furthermore, both obesity and diabetes are related to augmenting hepcidin release. Marmur et al. [53], showed that in NAFLD subjects, hepcidin levels in serum and liver correlate to body iron stores. These authors found no association with body mass index (BMI), lipid parameters, the degree of steatohepatitis, or C reactive protein. In patients with DIOS and NAFLD, serum hepcidin levels are close to those observed in other hepatic diseases with iron overload, except for hereditary hemochromatosis. Researchers postulate that an adequate hepcidin production in NAFLD in comparison to iron stores and the accumulation of iron in DIOS cannot be explained by a deficiency of hepcidin, differently from what is observed in hereditary hemochromatosis.
In animal models, the expression of hepcidin is inhibited in insulin resistance conditions. After administration of glucose, levels of hepcidin are elevated as well as in overweight and patients with NAFLD. The levels of hepcidin are also increased in patients with DIOS when comparing to obese patients with regular levels of ferritin. Elevated levels of hepcidin in DIOS may suggest hepcidin resistance [59].

4. Metabolic Syndrome

MtS is a cluster of conditions associated with the development of CVD. These factors may include insulin resistance, low levels of HDL-c, high levels of triglycerides, hypertension, altered values for waist circumference (WC), and obesity. These factors are associated with a complex dysregulation of iron homeostasis. Ferritin concentrations in serum increase with the number of risk factors of the MtS, especially insulin resistance, visceral fat mass, BMI, and hypertension. For these reasons, high ferritin levels have been related to a higher risk for the development of DM2 [5][45][60][61][62][63][64][65][66].
Furthermore, in subjects with morbid obesity, ferritin is strongly associated with IR and waist circumference. This may indicate that serum ferritin levels are closely related to important insulin resistance in overweight or obesity patients independent from other risk factors of the MtS. Particularly, serum ferritin concentrations can indicate severe liver insulin resistance and a higher risk for progression of relevant clinical hard endpoints such as cardiovascular death [67][68][69].
Serum ferritin levels are moderately elevated in MtS, but serum iron and transferrin saturation are usually normal, although transferrin saturation can be increased in up to 35% of cases. It is estimated that a third of MtS patients suffer from hyperferritinemia, although with normal transferrin saturation levels. The levels of hepcidin in serum can also be elevated in MtS [70][71].
An observational study with 1391 subjects (616 men and 775 women) showed that patients with MtS present significantly higher serum levels of ferritin and hepcidin than subjects without the syndrome. Iron regulatory feedback is preserved in MtS, and hepcidin tends to progressively augment in response to the augmented iron stores [72].
Risk factors of the MtS can also be related to inflammatory processes. Regardless of its cause, acute or chronic inflammation can augment ferritin levels in serum. Transferrin saturation may decrease or remain normal depending on DIOS parameters in this condition. In inflammatory processes, several cytokines are released, and especially IL-6 has a particular role in stimulating the production of ferritin and hepcidin. When there is an increase in hepcidin levels, iron sequestration in macrophages and enterocytes results in ferritin synthesis [26][43][68][71].

5. Oxidative Stress

OS in the cells is related to a significant imbalance of a plethora of biological signaling pathways. Reactive oxygen species (ROS) release usually happens via the reduction of molecular oxygen or due to oxidation of water. In balanced conditions, mitochondria produce ROS in consequence of aerobic respiration. Three to five percent of the oxygen is converted to ROS during this process. These molecular events require endogen enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. When the ROS production surpasses the cell’s antioxidant capacity, a disrupted condition (OS) starts and causes cellular macromolecules damages such as nucleic acids, lipids, and proteins may occur. Increased levels of ROS can also accelerate cell apoptosis and necrosis due to the activation of poly (adenosine diphosphate ribose) polymerase related to the development of several pathological conditions. On the other hand, ROS are needed in the heart under basal conditions for regulating myocyte growth, maintaining vascular smooth muscle tone, and other critical cellular responses. OS is also related to the development of incapacitant and degenerative conditions, such as neurological and cancer [73][74][75][76][77][78][79][80].
OS is the main reason why iron and IR damage the liver tissue in both animals and humans. The consequences are related to damage to DNA, lipids, and protein, glutathione depletion, energy loss, increased release of pro-inflammatory cytokines, fibrogenesis, steatosis, and cell death. Iron may also induce liver injury due to its role in the up-regulation of cholesterol production, stress induction in the endoplasmic reticulum, and activation of macrophages and stellate cells [8][81][82]. Furthermore, iron is also associated with an increase in the release of inflammatory cytokines, associated with fibrosis, steatosis, and hepatocellular carcinoma [8][80][83][84]. 
The hepatic steatosis seems to result in an environment of the augmented OS, as well as IR, and necrotic signalization in obese patients leading to hepatic damage [80][85]. DM2 and fluctuations in glycemia may be related to several micro and macrovascular complications that may result from OS and inflammatory processes leading to endothelial dysfunction and aberrant angiogenic capacity. Furthermore, atherosclerosis is a chronic process that affects large and medium-sized arteries and is also a consequence of OS [81][86][87][88].
Iron is also now related to a new non-apoptotic form of cells-death, called ferroptosis. This phenomenon is caused mainly by redox imbalance and can occur through two mechanisms: transporter-dependent (extrinsic) and enzyme-dependent (intrinsic). In resume, when a cell produces more oxidants than antioxidants, an abnormal presence of ROS. In iron-overload syndrome, the production of ROS and lipid peroxidation are all events mediated by iron ions. Extrinsic ferroptosis is caused mainly by elevation of iron uptake in consequence of decreased cysteine or glutamine uptake. The intrinsic form is caused principally by inhibition of glutathione peroxidase 4 (GPX4). All these forms lead in final analyses to the accumulation of ROS and this accumulation to oxidative damage. Ferroptosis is finished if oxidation reaches the cell membrane. Although ferroptosis is a relatively new concept, it is implicated in various human diseases, such as neurodegenerative diseases, CVD, infectious, and cancer [42][89][90].

6. Dysmetabolic Iron Overload Syndrome

DIOS was defined in the 1990s and shows a close relationship between hepatic iron overload and features of MtS in subjects without apparent cause of iron overload. It is more frequent than genetic hemochromatosis, and most patients are middle-aged males [8][12][13][22][47][91][92][93]. Now that MtS is increasing worldwide, the presence of DIOS follows this tendency.
DIOS is usually asymptomatic and can be diagnosed in the investigation of MtS and steatosis. Ferritin levels in the serum are increased (up to 1000–1200 ng/mL), but iron levels and transferrin saturation are usually normal. About 50% of the patients present altered hepatic biochemical tests (increased levels of γ-glutamyl transpeptidase itself or associated with increased levels of alanine aminotransferase). The liver may present parenchymal and mesenchymal iron overload, but the excess of iron is commonly mild. Steatosis (defined by the accumulation of triglycerides and fatty acids in the liver) or steatohepatitis was observed in half of the patients. Fibrosis or cirrhosis are observed in about 15% of patients [16][91][94][95][96].
The mechanisms of occurrence of an iron overload in DIOS are not entirely understood. Impairment in hepcidin synthesis and an imbalanced regulation of iron export are involved. The modification of metabolism of iron observed in patients with DIOS may result from a complex process triggered by the excess of iron in the diet together with environmental and genetic factors associated with a crosstalk between the hepatic tissue and visceral adipose tissue [11][12][22][59][93][94][97].
In a rat model of NAFLD, Fujiwara et al. [13] evaluated the role of iron overload. The animals were treated with a high-fat and high-fructose diet leading to hepatic steatosis, dyslipidemia and increase in the body weight. Furthermore, they observed increased hepatic inflammation represented by iron deposition in sinusoidal macrophages/Kupffer cells, together with nuclear translocation of nuclear factor-κB (NF κB) and increase of pro-inflammatory cytokines (such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN γ), and interleukin (IL)-1β) due to the upregulation of TH1/M1.
Studies with dietary iron loading animals showed increased resistin expression and reduced leptin levels. Increased resistin and decreased leptin levels contribute respectively to IR and increased appetite. These two conditions together increase the chances of developing obesity and DM. The metabolism of adipose tissue results in increased resistin, TNF-α, IFN-γ, interleukins (IL-6, IL-8, and IL-12), free fat acids (FFA), and a decrease in leptin, and IL-10 levels. This secretory pattern leads to an increase in the inflammatory activity in obese patients (low-grade inflammation) [98][99] showed that leptin directly interferes with iron metabolism. These authors showed that leptin levels were lower in leptin-deficient mice and higher in leptin receptor-deficient when compared with control. These results suggest that the activation of the leptin receptor has effects on hepcidin expression. Researchers concluded that this inappropriate signaling of this hormone could nearly link obesity, MtS, CVD, autoimmunity, and cancer. In this sense, iron-mediated OS could also be contributing to this unfavorable scenario.
The iron metabolism is commonly imbalanced in obese patients in both cellular and tissue levels. Moreover, adipose tissue plays an essential role in iron regulation. The presence of obesity may modify macrophage iron content in visceral adipose tissue in the liver and adipocytes. Furthermore, iron reduces the expression of adiponectin that is related to improving IR. The level of this adipokine is reduced in MtS subjects and negatively correlated with serum ferritin levels [8][71][100][101][102].
Higher ferritin levels are associated with obesity and overweight children and may be influenced by a liver injury that, associated with hypertrophied adipocytes and low-grade inflammation, follow the clinical course of overweight and obesity to modify the circulating markers of iron status. Still, the decreased absorption of iron observed in obesity can be the consequence of higher hepcidin levels that are also triggered by inflammatory processes. On the other hand, the levels of serum transferrin and serum iron decreases during inflammation [71][103][104][105].
Modifications in iron metabolism (ferritin or serum iron) are also associated with altered lipid concentration in adults and children [106]. Gonzalez-Dominguez et al. and Zhu et al. [61][71] showed that dyslipidemic children and adolescents presented lower levels of serum iron and increased ferritin levels in the obese.

7. Future Directions

An increase in the hepatic and body iron stores and the presence of MtS components characterizes DIOS. Although increasing evidence suggests an overlap between NAFLD with iron overload and, therefore, DIOS, the pathogenic pathways involved in DIOS occurrence are still not completely understood. Due to these reasons, soon, not only animal models sharing similarities with human patients with DIOS must be designed, but also non-invasive methods for iron overload evaluation in dysmetabolic human patients must be improved. Furthermore, there is a need to investigate how iron overload overlaps with NAFLD and causes dysmetabolic changes in the body’s homeostasis [13][47]. Since a mild to moderate excess of iron in the liver can aggravate the risk of NAFLD progression to NASH, it is also necessary to unravel the mechanistic events by which pro-inflammatory cytokines, ROS, OS, and lipid peroxidation can be related to iron overload toxicity [22].
The pathways of how DIOS affects other diseases, such as inflammatory and immunomodulated diseases, must also be a field of study. Researchers highlighted that in DIOS, macrophages might present impaired polarization toward the M2 alternative phenotype, which is considered an adaptative role of the up-regulation of the TFRC in DIOS macrophages that may limit iron toxicity during the dysmetabolic process [91]. However, these events can affect the occurrence and progression of diseases other than DIOS, like atherosclerosis, arthritis, cardiometabolic affections, and other degenerative conditions. The relationship between iron status and obesity is another field that must be highlighted [107], principally because individuals with augmented visceral adiposity and waist circumference do not necessarily have increased body mass index.

This entry is adapted from the peer-reviewed paper 10.3390/endocrines4010002

References

  1. Barbalho, S.M.; Tofano, R.J.; Chagas, E.F.B.; Detregiachi, C.R.P.; Goulart, A.R.; Flato, U.A.P. Benchside to the bedside of frailty and cardiovascular aging: Main shared cellular and molecular mechanisms. Exp. Gerontol. 2021, 148, 111302.
  2. Liberale, L.; Badimon, L.; Montecucco, F.; Lüscher, T.F.; Libby, P.; Camici, G.G. Inflammation, Aging, and Cardiovascular Disease: JACC Review Topic of the Week. J. Am. Coll. Cardiol. 2022, 79, 837–847.
  3. Aboonabi, A.; Meyer, R.R.; Singh, I. The association between metabolic syndrome components and the development of atherosclerosis. J. Hum. Hypertens. 2019, 33, 844–855.
  4. Saedi, S.; Watson, S.E.; Young, J.L.; Tan, Y.; Wintergerst, K.A.; Cai, L. Does maternal low-dose cadmium exposure increase the risk of offspring to develop metabolic syndrome and/or type 2 diabetes? Life Sci. 2023, 9, 121385.
  5. Silveira Rossi, J.L.; Barbalho, S.M.; Reverete de Araujo, R.; Bechara, M.D.; Sloan, K.P.; Sloan, L.A. Metabolic syndrome and cardiovascular diseases: Going beyond traditional risk factors. Diabetes/Metab. Res. Rev. 2022, 38, e3502.
  6. Sinatora, R.V.; Chagas, E.F.B.; Mattera, F.O.P.; Mellem, L.J.; Santos, A.; Pereira, L.P.; Aranão, A.L.C.; Guiguer, E.L.; Araújo, A.C.; Haber, J.; et al. Relationship of Inflammatory Markers and Metabolic Syndrome in Postmenopausal Women. Metabolites 2022, 12, 73.
  7. Dos Santos Vieira, D.A.; Hermes Sales, C.; Galvão Cesar, C.L.; Marchioni, D.M.; Fisberg, R.M. Influence of Haem, Non-Haem, and Total Iron Intake on Metabolic Syndrome and Its Components: A Population-Based Study. Nutrients 2018, 10, 314.
  8. Li, H.; Lin, L.; Xia, Y.L.; Xie, Y.; Yang, X. Research progress on the role of ferroptosis in cardiovascular disease. Front Cardiovasc Med. 2022, 22, 1077332.
  9. Lainé, F.; Reymann, J.M.; Morel, F.; Langouët, S.; Perrin, M.; Guillygomarc’h, A.; Brissot, P.; Turmel, V.; Mouchel, C.; Pape, D.; et al. Effects of phlebotomy therapy on cytochrome P450 2e1 activity and oxidative stress markers in dysmetabolic iron overload syndrome: A randomized trial. Aliment. Pharmacol. Ther. 2006, 24, 1207–1213.
  10. Qiu, R.; Alikhanyan, K.; Volk, N.; Marques, O.; Mertens, C.; Agarvas, A.R.; Singh, S.; Pepperkok, R.; Altamura, S.; Muckenthaler, M.U. Repression of the iron exporter ferroportin may contribute to hepatocyte iron overload in individuals with type 2 diabetes. Mol. Metab. 2022, 66, 101644.
  11. Sachinidis, A.; Doumas, M.; Imprialos, K.; Stavropoulos, K.; Katsimardou, A.; Athyros, V.G. Dysmetabolic Iron Overload in Metabolic Syndrome. Curr. Pharm. Des. 2020, 26, 1019–1024.
  12. Castiella, A.; Urreta, I.; Zapata, E.; de Juan, M.; Alústiza, J.M.; Emparanza, J.I. Dysmetabolic iron overload syndrome and its relationship with HFE gene mutations and with liver steatosis. Dig. Liver Dis. 2020, 52, 683–685.
  13. Fujiwara, S.; Izawa, T.; Mori, M.; Atarashi, M.; Yamate, J.; Kuwamura, M. Dietary iron overload enhances Western diet induced hepatic inflammation and alters lipid metabolism in rats sharing similarity with human DIOS. Sci. Rep. 2022, 12, 21414.
  14. Méndez-Sánchez, N.; Bugianesi, E.; Gish, R.G.; Lammert, F.; Tilg, H.; Nguyen, M.H.; Sarin, S.K.; Fabrellas, N.; Zelber-Sagi, S.; Fan, J.G.; et al. Global multi-stakeholder endorsement of the MAFLD definition. Lancet Gastroenterol. Hepatol. 2022, 7, 388–390.
  15. Gattermann, N.; Muckenthaler, M.U.; Kulozik, A.E.; Metzgeroth, G.; Hastka, J. The Evaluation of Iron Deficiency and Iron Overload. Dtsch. Arztebl. Int. 2021, 118, 847–856.
  16. Moris, W.; Verhaegh, P.; Jonkers, D.; Deursen, C.V.; Koek, G. Hyperferritinemia in Nonalcoholic Fatty Liver Disease: Iron Accumulation or Inflammation? Semin. Liver Dis. 2019, 39, 476–482.
  17. Crawford, D.H.G.; Ross, D.G.F.; Jaskowski, L.-A.; Burke, L.J.; Britton, L.J.; Musgrave, N.; Briskey, D.; Rishi, G.; Bridle, K.R.; Subramaniam, V.N. Iron depletion attenuates steatosis in a mouse model of non-alcoholic fatty liver disease: Role of iron-dependent pathways. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2021, 1867, 166142.
  18. Deugnier, Y.; Turlin, B. Iron and hepatocellular carcinoma. J. Gastroenterol. Hepatol. 2001, 16, 491–494.
  19. Tam, E.; Sung, H.K.; Lam, N.H.; You, S.; Cho, S.; Ahmed, S.M.; Abdul-Sater, A.A.; Sweeney, G. Role of Mitochondrial Iron Overload in Mediating Cell Death in H9c2 Cells. Cells 2022, 28, 118.
  20. Maliken, B.D.; Nelson, J.E.; Klintworth, H.M.; Beauchamp, M.; Yeh, M.M.; Kowdley, K.V. Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease. Hepatology 2013, 57, 1806–1813.
  21. Nelson, J.E.; Wilson, L.; Brunt, E.M.; Yeh, M.M.; Kleiner, D.E.; Unalp-Arida, A.; Kowdley, K.V. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011, 53, 448–457.
  22. Fernandez, M.; Lokan, J.; Leung, C.; Grigg, A. A critical evaluation of the role of iron overload in fatty liver disease. J. Gastroenterol. Hepatol. 2022, 37, 1873–1883.
  23. Ameka, M.; Hasty, A.H. Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease. Compr. Physiol. 2022, 12, 3641–3663.
  24. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357.
  25. Younossi, Z.; Golabi, P.; Paik, J.; Henry, A.; Van Dongen, C.; Henry, L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH): A systematic review. Hepatology. 2023.
  26. Camaschella, C.; Nai, A.; Silvestri, L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica 2020, 105, 260–272.
  27. Chen, X.; Yu, C.; Kang, R.; Tang, D. Iron Metabolism in Ferroptosis. Front. Cell Dev. Biol. 2020, 8, 590226.
  28. Xiang, Y.; Fan, X.; Zhao, M.; Guo, Q.; Guo, S. CKIP-1 alleviates oxygen-glucose deprivation/reoxygenation-induced apoptosis and oxidative stress in cultured hippocampal neurons by downregulating Keap1 and activating Nrf2/ARE signaling. Eur. J. Pharmacol. 2019, 848, 140–149.
  29. Chen, H.; Zhao, W.; Yan, X.; Huang, T.; Yang, A. Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis. J. Clin. Transl. Hepatol. 2022, 10, 577–588.
  30. Kim, C.H.; Leitch, H.A. Iron overload-induced oxidative stress in myelodysplastic syndromes and its cellular sequelae. Crit. Rev. Oncol./Hematol. 2021, 163, 103367.
  31. Gordan, R.; Fefelova, N.; Gwathmey, J.K.; Xie, L.-H. Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore. Antioxidants 2020, 9, 758.
  32. Loomba, R.; Sanyal, A.J. The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 686–690.
  33. Lazo, M.; Hernaez, R.; Eberhardt, M.S.; Bonekamp, S.; Kamel, I.; Guallar, E.; Koteish, A.; Brancati, F.L.; Clark, J.M. Prevalence of nonalcoholic fatty liver disease in the United States: The Third National Health and Nutrition Examination Survey, 1988-1994. Am. J. Epidemiol. 2013, 178, 38–45.
  34. Murali, A.R.; Gupta, A.; Brown, K. Systematic review and meta-analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease. Hepatol. Res. 2018, 48, E30–E41.
  35. Satiya, J.; Snyder, H.S.; Singh, S.P.; Satapathy, S.K. Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis. Transl. Gastroenterol. Hepatol. 2021, 6, 60.
  36. Huang, D.Q.; El-Serag, H.B.; Loomba, R. Global epidemiology of NAFLD-related HCC: Trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 223–238.
  37. Carpi, R.Z.; Barbalho, S.M.; Sloan, K.P.; Laurindo, L.F.; Gonzaga, H.F.; Grippa, P.C.; Zutin, T.L.M.; Girio, R.J.S.; Repetti, C.S.F.; Detregiachi, C.R.P.; et al. The Effects of Probiotics, Prebiotics and Synbiotics in Non-Alcoholic Fat Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH): A Systematic Review. Int. J. Mol. Sci. 2022, 23, 8805.
  38. Chen, H.; Zhan, Y.; Zhang, J.; Cheng, S.; Zhou, Y.; Chen, L.; Zeng, Z. The Global, Regional, and National Burden and Trends of NAFLD in 204 Countries and Territories: An Analysis From Global Burden of Disease 2019. JMIR Public Health Surveill. 2022, 8, e34809.
  39. Kadoglou, N.P.; Biddulph, J.P.; Rafnsson, S.B.; Trivella, M.; Nihoyannopoulos, P.; Demakakos, P. The association of ferritin with cardiovascular and all-cause mortality in community-dwellers: The English longitudinal study of ageing. PLoS ONE 2017, 12, e0178994.
  40. Shander, A.; Goodnough, L.T.; Javidroozi, M.; Auerbach, M.; Carson, J.; Ershler, W.B.; Ghiglione, M.; Glaspy, J.; Lew, I. Iron deficiency anemia—Bridging the knowledge and practice gap. Transfus. Med. Rev. 2014, 28, 156–166.
  41. Takatoku, M. Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur. J. Haematol. 2007, 78, 487–494.
  42. Plays, M.; Müller, S.; Rodriguez, R. Chemistry and biology of ferritin. Metallomics 2021, 13, mfab021.
  43. Lorcerie, B.; Audia, S.; Samson, M.; Millière, A.; Falvo, N.; Leguy-Seguin, V.; Berthier, S.; Bonnotte, B. Diagnosis of hyperferritinemia in routine clinical practice. La Presse Méd. 2017, 46, e329–e338.
  44. Sandnes, M.; Ulvik, R.J.; Vorland, M.; Reikvam, H. Hyperferritinemia—A Clinical Overview. J. Clin. Med. 2021, 10, 2008.
  45. Tofano, R.J.; Pescinni-Salzedas, L.M.; Chagas, E.F.B.; Detregiachi, C.R.P.; Guiguer, E.L.; Araujo, A.C.; Bechara, M.D.; Rubira, C.J.; Barbalho, S.M. Association of Metabolic Syndrome and Hyperferritinemia in Patients at Cardiovascular Risk. Diabetes Metab. Syndr. Obes. Targets Ther. 2020, 13, 3239–3248.
  46. Barreto, B.F.M.; Punaro, G.R.; Elias, M.C.; Parise, E.R. Is homeostasis model assessment for insulin resistance > 2.5 a distinguished criteria for metabolic dysfunction-associated fatty liver disease identification? Arq. Gastroenterol. 2022, 59, 402–407.
  47. Branisso, P.P.F.; de Oliveira, C.; Filho, H.M.L.; Lima, F.R.; Santos, A.S.; Mancini, M.C.; de Melo, M.E.; Carrilho, F.J.; Rocha, M.S.; Clark, P.; et al. Non-invasive methods for iron overload evaluation in dysmetabolic patients. Ann. Hepatol. 2022, 27, 100707.
  48. Fan, Y.; Wang, J.; Wei, L.; He, B.; Wang, C.; Wang, B. Iron deficiency activates pro-inflammatory signaling in macrophages and foam cells via the p38 MAPK-NF-κB pathway. Int. J. Cardiol. 2011, 152, 49–55.
  49. Sung, K.C.; Kang, J.H.; Shin, H.S. Relationship of cardiovascular risk factors and serum ferritin with C-reactive protein. Arch. Med. Res. 2007, 38, 121–125.
  50. Choi, Y.S.; Jang, H.; Gupta, B.; Jeong, J.H.; Ge, Y.; Yong, C.S.; Kim, J.O.; Bae, J.S.; Song, I.S.; Kim, I.S.; et al. Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities. J. Hematol. Oncol. 2020, 13, 123.
  51. Adamska, A.; Łebkowska, A.; Krentowska, A.; Adamski, M.; Kowalska, I. The Association Between Serum Ferritin Concentration and Visceral Adiposity Estimated by Whole-Body DXA Scan in Women With Polycystic Ovary Syndrome. Front. Endocrinol. 2020, 10, 873.
  52. Trasolini, R.; Cox, B.; Galts, C.; Yoshida, E.M.; Marquez, V. Elevated serum ferritin in non-alcoholic fatty liver disease is not predictive of fibrosis. Can. Liver J. 2022, 5, 152–159.
  53. Marmur, J.; Beshara, S.; Eggertsen, G.; Onelöv, L.; Albiin, N.; Danielsson, O.; Hultcrantz, R.; Stål, P. Hepcidin levels correlate to liver iron content, but not steatohepatitis, in non-alcoholic fatty liver disease. BMC Gastroenterol. 2018, 18, 78.
  54. Kanamori, Y.; Murakami, M.; Sugiyama, M.; Hashimoto, O.; Matsui, T.; Funaba, M. Hepcidin and IL-1β. Vitam. Horm. 2019, 110, 143–156.
  55. Kowdley, K.V.; Gochanour, E.M.; Sundaram, V.; Shah, R.A.; Handa, P. Hepcidin Signaling in Health and Disease: Ironing Out the Details. Hepatol. Commun. 2021, 5, 723–735.
  56. Zhou, W.; Qiu, K. The correlation between lncRNA NEAT1 and serum hepcidin in the peripheral blood of non-alcoholic fatty liver disease patients. Am. J. Transl. Res. 2022, 14, 2593–2599.
  57. Gozzelino, R.; Arosio, P. Iron homeostasis in health and disease. Int. J. Mol. Sci. 2016, 17, 130.
  58. Meynard, D.; Babitt, J.L.; Lin, H.Y. The Journal of the American Society of Hematology. The liver: Conductor of systemic iron balance. Blood J. Am. Soc. Hematol. 2014, 123, 168–176.
  59. Rametta, R.; Dongiovanni, P.; Pelusi, S.; Francione, P.; Iuculano, F.; Borroni, V.; Fatta, E.; Castagna, A.; Girelli, D.; Fargion, S. Hepcidin resistance in dysmetabolic iron overload. Liver Int. 2016, 36, 1540–1548.
  60. Stechemesser, L.; Eder, S.K.; Wagner, A.; Patsch, W.; Feldman, A.; Strasser, M.; Auer, S.; Niederseer, D.; Huber-Schönauer, U.; Paulweber, B. Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism. Mol. Metab. 2017, 6, 38–47.
  61. Zhu, Y.; He, B.; Xiao, Y.; Chen, Y. Iron metabolism and its association with dyslipidemia risk in children and adolescents: A cross-sectional study. Lipids Health Dis. 2019, 18, 50.
  62. Datz, C.; Müller, E.; Aigner, E. Iron overload and non-alcoholic fatty liver disease. Minerva Endocrinol. 2016, 42, 173–183.
  63. Iwasaki, T.; Nakajima, A.; Yoneda, M.; Yamada, Y.; Mukasa, K.; Fujita, K.; Fujisawa, N.; Wada, K.; Terauchi, Y. Serum ferritin is associated with visceral fat area and subcutaneous fat area. Diabetes Care 2005, 28, 2486–2491.
  64. Piperno, A.; Trombini, P.; Gelosa, M.; Mauri, V.; Pecci, V.; Vergani, A.; Salvioni, A.; Mariani, R.; Mancia, G. Increased serum ferritin is common in men with essential hypertension. J. Hypertens. 2002, 20, 1513–1518.
  65. Kao, T.-W.; Huang, C.-C. Recent Progress in Metabolic Syndrome Research and Therapeutics. Int. J. Mol. Sci. 2021, 22, 6862.
  66. Lyu, J.; Lin, Q.; Fang, Z.; Xu, Z.; Liu, Z. Complex impacts of gallstone disease on metabolic syndrome and nonalcoholic fatty liver disease. Front. Endocrinol. 2022, 13, 1032557.
  67. Ellervik, C.; Marott, J.L.; Tybjærg-Hansen, A.; Schnohr, P.; Nordestgaard, B.G. Total and cause-specific mortality by moderately and markedly increased ferritin concentrations: General population study and metaanalysis. Clin. Chem. 2014, 60, 1419–1428.
  68. Rametta, R.; Fracanzani, A.L.; Fargion, S.; Dongiovanni, P. Dysmetabolic Hyperferritinemia and Dysmetabolic Iron Overload Syndrome (DIOS): Two Related Conditions or Different Entities? Curr. Pharm. Des. 2020, 26, 1025–1035.
  69. Li, N.; Liao, Y.; Huang, H.; Fu, S. Co-regulation of hepatic steatosis by ferritinophagy and unsaturated fatty acid supply. Hepatol. Commun. 2022, 6, 2640–2653.
  70. Mendler, M.-H.; Turlin, B.; Moirand, R.; Jouanolle, A.-M.; Sapey, T.; Guyader, D.; le Gall, J.-Y.; Brissot, P.; David, V.; Deugnier, Y. Insulin resistance–associated hepatic iron overload. Gastroenterology 1999, 117, 1155–1163.
  71. González-Domínguez, Á.; Visiedo-García, F.M.; Domínguez-Riscart, J.; González-Domínguez, R.; Mateos, R.M.; Lechuga-Sancho, A.M. Iron Metabolism in Obesity and Metabolic Syndrome. Int. J. Mol. Sci. 2020, 21, 5529.
  72. Martinelli, N.; Traglia, M.; Campostrini, N.; Biino, G.; Corbella, M.; Sala, C.; Busti, F.; Masciullo, C.; Manna, D.; Previtali, S.; et al. Increased serum hepcidin levels in subjects with the metabolic syndrome: A population study. PLoS ONE 2012, 7, e48250.
  73. Pisoschi, A.M.; Pop, A.; Iordache, F.; Stanca, L.; Predoi, G.; Serban, A.I. Oxidative stress mitigation by antioxidants-An overview on their chemistry and influences on health status. Eur. J. Med. Chem. 2021, 209, 112891.
  74. Singh, E.; Devasahayam, G. Neurodegeneration by oxidative stress: A review on prospective use of small molecules for neuroprotection. Mol. Biol. Rep. 2020, 47, 3133–3140.
  75. García-Guede, Á.; Vera, O.; Ibáñez-de-Caceres, I. When Oxidative Stress Meets Epigenetics: Implications in Cancer Development. Antioxidants 2020, 9, 468.
  76. Ghosh, R.; Alajbegovic, A.; Gomes, A.V. NSAIDs and cardiovascular diseases: Role of reactive oxygen species. Oxidative Med. Cell. Longev. 2015, 2015, 536962.
  77. Brown, G.C.; Murphy, M.P.; Jastroch, M.; Divakaruni, A.S.; Mookerjee, S.; Treberg, J.R.; Brand, M.D. Mitochondrial proton and electron leaks. Essays Biochem. 2010, 47, 53–67.
  78. Chen, Q.; Vazquez, E.J.; Moghaddas, S.; Hoppel, C.L.; Lesnefsky, E.J. Production of reactive oxygen species by mitochondria: Central role of complex III. J. Biol. Chem. 2003, 278, 36027–36031.
  79. Watson, A.J.; Askew, J.N.; Benson, R.S. Poly (adenosine diphosphate ribose) polymerase inhibition prevents necrosis induced by H2O2 but not apoptosis. Gastroenterology 1995, 109, 472–482.
  80. Hernandez, A.; Sonavane, M.; Smith, K.R.; Seiger, J.; Migaud, M.E.; Gassman, N.R. Dihydroxyacetone suppresses mTOR nutrient signaling and induces mitochondrial stress in liver cells. PLoS ONE 2022, 17, e0278516.
  81. Maamoun, H.; Benameur, T.; Pintus, G.; Munusamy, S.; Agouni, A. Crosstalk between oxidative stress and endoplasmic reticulum (ER) stress in endothelial dysfunction and aberrant angiogenesis associated with diabetes: A focus on the protective roles of heme oxygenase (HO)-1. Front. Physiol. 2019, 10, 70.
  82. Shin, G.C.; Lee, H.M.; Kim, N.; Yoo, S.K.; Park, H.S.; Choi, L.S.; Kim, K.P.; Lee, A.R.; Seo, S.U.; Kim, K.H. Paraoxonase-2 contributes to promoting lipid metabolism and mitochondrial function via autophagy activation. Sci. Rep. 2022, 12, 21483.
  83. Britton, L.J.; Subramaniam, V.N.; Crawford, D.H. Iron and non-alcoholic fatty liver disease. World J. Gastroenterol. 2016, 22, 8112.
  84. Hwang, K.A.; Hwang, Y.; Hwang, H.J.; Park, N. Hepatoprotective Effects of Radish (Raphanus sativus L.) on Acetaminophen-Induced Liver Damage via Inhibiting Oxidative Stress and Apoptosis. Nutrients 2022, 14, 5082.
  85. Ganz, T.; Nemeth, E. Iron homeostasis in host defence and inflammation. Nat. Rev. Immunol. 2015, 15, 500–510.
  86. Cabezas, K.G.; Gómez-Fernandez, C.R.; Vazquez-Padron, R. A comprehensive review of oxidative stress as the underlying mechanism in atherosclerosis and the inefficiency of antioxidants to revert this process. Curr. Pharm. Des. 2018, 24, 4705–4710.
  87. Du, R.; Wu, X.; Peng, K.; Lin, L.; Li, M.; Xu, Y.; Xu, M.; Chen, Y.; Li, D.; Lu, J. Serum apolipoprotein B is associated with increased risk of metabolic syndrome among middle-aged and elderly Chinese: A cross-sectional and prospective cohort study. J. Diabetes 2019, 11, 752–760.
  88. Barbalho, S.M.; Bueno Ottoboni, A.M.M.; Fiorini, A.M.R.; Guiguer, É.L.; Nicolau, C.C.T.; Goulart, R.d.A.; Flato, U.A.P. Grape juice or wine: Which is the best option? Crit. Rev. Food Sci. Nutr. 2020, 60, 3876–3889.
  89. Tang, D.; Chen, X.; Kang, R.; Kroemer, G. Ferroptosis: Molecular mechanisms and health implications. Cell Res. 2021, 31, 107–125.
  90. Zhang, M.W.; Li, X.T.; Zhang, Z.Z.; Liu, Y.; Song, J.W.; Liu, X.M.; Chen, Y.H.; Wang, N.; Guo, Y.; Liang, L.R.; et al. Elabela blunts doxorubicin-induced oxidative stress and ferroptosis in rat aortic adventitial fibroblasts by activating the KLF15/GPX4 signaling. Cell Stress Chaperones 2022, 1–13.
  91. Lahaye, C.; Gladine, C.; Pereira, B.; Berger, J.; Chinetti-Gbaguidi, G.; Lainé, F.; Mazur, A.; Ruivard, M. Does iron overload in metabolic syndrome affect macrophage profile? A case control study. J. Trace Elem. Med. Biol. 2021, 67, 126786.
  92. Castiella, A.; Urreta, I.; Zapata, E.; Zubiaurre, L.; Alústiza, J.M.; Otazua, P.; Salvador, E.; Letamendi, G.; Arrizabalaga, B.; Rincón, M.L.; et al. Liver iron concentration in dysmetabolic hyperferritinemia: Results from a prospective cohort of 276 patients. Ann. Hepatol. 2020, 19, 31–35.
  93. Bardou-Jacquet, E.; Lainé, F.; Morcet, J.; Perrin, M.; Guyader, D.; Deugnier, Y. Long-term course after initial iron removal of iron excess in patients with dysmetabolic iron overload syndrome. Eur. J. Gastroenterol. Hepatol. 2014, 26, 418–421.
  94. Rauber, M.R.; Pilger, D.A.; Cecconello, D.K.; Falcetta, F.S.; Marcondes, N.A.; Faulhaber, G.A.M. Hepcidin is a useful biomarker to evaluate hyperferritinemia associated with metabolic syndrome. Acad. Bras. Cienc. 2019, 91, e20180286.
  95. Dongiovanni, P.; Fracanzani, A.L.; Fargion, S.; Valenti, L. Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target. J. Hepatol. 2011, 55, 920–932.
  96. Turlin, B.; Mendler, M.H.; Moirand, R.; Guyader, D.; Guillygomarc’h, A.; Deugnier, Y. Histologic features of the liver in insulin resistance–associated iron overload: A study of 139 patients. Am. J. Clin. Pathol. 2001, 116, 263–270.
  97. Ruivard, M.; Lainé, F.; Ganz, T.; Olbina, G.; Westerman, M.; Nemeth, E.; Rambeau, M.; Mazur, A.; Gerbaud, L.; Tournilhac, V. Iron absorption in dysmetabolic iron overload syndrome is decreased and correlates with increased plasma hepcidin. J. Hepatol. 2009, 50, 1219–1225.
  98. Moreno-Navarrete, J.M.; Novelle, M.G.; Catalán, V.; Ortega, F.; Moreno, M.; Gomez-Ambrosi, J.; Xifra, G.; Serrano, M.; Guerra, E.; Ricart, W. Insulin resistance modulates iron-related proteins in adipose tissue. Diabetes Care 2014, 37, 1092–1100.
  99. Yamamoto, K.; Kuragano, T.; Kimura, T.; Nanami, M.; Hasuike, Y.; Nakanishi, T. Interplay of adipocyte and hepatocyte: Leptin upregulates hepcidin. Biochem. Biophys. Res. Commun. 2018, 495, 1548–1554.
  100. Orr, J.S.; Kennedy, A.; Anderson-Baucum, E.K.; Webb, C.D.; Fordahl, S.C.; Erikson, K.M.; Zhang, Y.; Etzerodt, A.; Moestrup, S.K.; Hasty, A.H. Obesity alters adipose tissue macrophage iron content and tissue iron distribution. Diabetes 2014, 63, 421–432.
  101. Dongiovanni, P.; Ruscica, M.; Rametta, R.; Recalcati, S.; Steffani, L.; Gatti, S.; Girelli, D.; Cairo, G.; Magni, P.; Fargion, S. Dietary iron overload induces visceral adipose tissue insulin resistance. Am. J. Pathol. 2013, 182, 2254–2263.
  102. Nazari, M.; Ho, K.W.; Langley, N.; Cha, K.M.; Kodsi, R.; Wang, M.; Laybutt, D.R.; Cheng, K.; Stokes, R.A.; Swarbrick, M.M.; et al. Iron chelation increases beige fat differentiation and metabolic activity, preventing and treating obesity. Sci. Rep. 2022, 12, 776.
  103. Khan, M.J.; Gerasimidis, K.; Edwards, C.A.; Shaikh, M.G. Role of gut microbiota in the aetiology of obesity: Proposed mechanisms and review of the literature. J. Obes. 2016, 2016, 7353642.
  104. Zhang, J.; Cao, J.; Xu, H.; Dong, G.; Huang, K.; Wu, W.; Ye, J.; Fu, J. Ferritin as a key risk factor for nonalcoholic fatty liver disease in children with obesity. J. Clin. Lab. Anal. 2020, 35, e23602.
  105. Zhao, L.; Zhang, X.; Shen, Y.; Fang, X.; Wang, Y.; Wang, F. Obesity and iron deficiency: A quantitative meta-analysis. Obes. Rev. 2015, 16, 1081–1093.
  106. Chen, P.K.; Yeo, K.J.; Huang, P.H.; Chang, S.H.; Chang, C.K.; Lan, J.L.; Chen, D.Y. Increased Lipid Peroxidation May Be Linked to Ferritin Levels Elevation in Adult-Onset Still’s Disease. Biomedicines 2021, 9, 1508.
  107. Vaquero, M.P.; Martínez-Maqueda, D.; Gallego-Narbón, A.; Zapatera, B.; Pérez-Jiménez, J. Relationship between iron status markers and insulin resistance: An exploratory study in subjects with excess body weight. PeerJ 2020, 8, e9528.
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