Metabolic and hepatic effects of bloodletting in dysmetabolic iron overload syndrome: A randomized controlled study in 274 patients

Lainé, Fabrice; Ruivard, M.; Loustaud‐Ratti, Véronique; Bonnet, Fabrice; Calès, Paul; Bardou-Jacquet, Édouard; Sacher‐Huvelin, Sylvie; Causse, Xavier; Beusnel, Christine; Renault, Alain; Bellissant, Éric; Deugnier, Yves

doi:10.1002/hep.28856

Cited by 55 publications

(85 citation statements)

References 27 publications

(85 reference statements)

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“…We excluded 13 articles; 4 had no data, 5 had different end‐points, and different intervention was applied in 4 studies. We included 9 studies for our systematic review . There was full agreement among the reviewers regarding study selection for the analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The dysmetabolic iron overload syndrome (DIOS) was originally described as a form of mild iron overload associated with one or more features of the metabolic syndrome . Although a majority of patients with DIOS have non‐alcoholic fatty liver disease (NAFLD), fatty liver is not universally present in this condition . Conversely, NAFLD, which is also a manifestation of insulin resistance and the metabolic syndrome, is commonly but not invariably accompanied by evidence of expanded body iron stores.…”

Section: Introductionmentioning

confidence: 99%

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Systematic review and meta‐analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non‐alcoholic fatty liver disease

Murali

Gupta

Brown

2017

Hepatology Research

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systematic review and meta‐analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non‐alcoholic fatty liver disease

Murali

Gupta

Brown

2017

Hepatology Research

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“…Furthermore, a recently published, randomized, controlled study by Laine et al16 of 274 participants with dysmetabolic iron overload and significantly elevated HIC (>50 mmol/kg) found that venesection was associated with significantly increased serum insulin and HOMA‐IR scores over time. We found no difference between groups in HOMA‐IR scores, ISI, or change in HOMA‐IR or ISI over time 17.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a randomized controlled trial of 274 adults with dysmetabolic iron overload syndrome showed that venesection did not affect serum adiponectin levels; however, other adipokines were not assessed 16. Venesection in a cohort of 6 patients with type 2 diabetes led to a reduction in serum levels of RBP‐4 12…”

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confidence: 99%

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease

Britton

Bridle

Reiling

et al. 2018

Hepatology Communications

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Rodent and cell‐culture models support a role for iron‐related adipokine dysregulation and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, substantial human data are lacking. We examined the relationship between measures of iron status, adipokines, and insulin resistance in patients with NAFLD in the presence and absence of venesection. This study forms part of the Impact of Iron on Insulin Resistance and Liver Histology in Nonalcoholic Steatohepatitis (IIRON2) study, a prospective randomized controlled trial of venesection for adults with NAFLD. Paired serum samples at baseline and 6 months (end of treatment) in controls (n = 28) and patients who had venesection (n = 23) were assayed for adiponectin, leptin, resistin, retinol binding protein‐4, tumor necrosis factor α, and interleukin‐6, using a Quantibody, customized, multiplexed enzyme‐linked immunosorbent assay array. Hepatic iron concentration (HIC) was determined using MR FerriScan. Unexpectedly, analysis revealed a significant positive correlation between baseline serum adiponectin concentration and HIC, which strengthened after correction for age, sex, and body mass index (rho = 0.36; P = 0.007). In addition, there were significant inverse correlations between HIC and measures of insulin resistance (adipose tissue insulin resistance (Adipo‐IR), serum insulin, serum glucose, homeostasis model assessment of insulin resistance, hemoglobin A1c, and hepatic steatosis), whereas a positive correlation was noted with the insulin sensitivity index. Changes in serum adipokines over 6 months did not differ between the control and venesection groups. Conclusion: HIC positively correlates with serum adiponectin and insulin sensitivity in patients with NAFLD. Further study is required to establish causality and mechanistic explanations for these associations and their relevance in the pathogenesis of insulin resistance and NAFLD. (Hepatology Communications 2018;2:644‐653)

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“…Despite preliminary evidence from human and animal studies implicating iron in the pathogenesis of NAFLD and insulin resistance, two randomized controlled trials and a recent meta‐analysis failed to demonstrate any short‐term benefit from iron depletion by venesection on insulin resistance and markers of liver damage in patients with NAFLD and/or dysmetabolic iron overload syndrome (DIOS) with mild iron overload . The reasons for this are unclear, but may relate to patient selection/study design, or even the location of pathogenic iron deposition in NAFLD being less amenable to venesection.…”

Section: Discussionmentioning

confidence: 99%

Hepatic iron is the major determinant of serum ferritin in NAFLD patients

Ryan

Armitage

Cobbold

et al. 2017

Liver International

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Background and Aims Elevated serum ferritin is common in NAFLD, and is associated with more advanced disease and increased mortality. Hyperferritinaemia in NAFLD is often attributed to inflammation, while in other conditions ferritin closely reflects body iron stores. The aim of this study was to clarify the underlying cause of hyperferritinaemia in NAFLD. Methods Ferritin levels were examined with markers of iron status, inflammation and liver injury across the clinical spectrum of NAFLD using blood, tissue and magnetic resonance (MR) imaging. A separate larger group of NAFLD patients with hepatic iron staining and quantification were used for validation. Results Serum ferritin correlated closely with the iron regulatory hormone hepcidin, and liver iron levels determined by MR. Furthermore, ferritin levels reflected lower serum adiponectin, a marker of insulin resistance, and liver fat, but not cytokine or CRP levels. Ferritin levels differed according to fibrosis stage, increasing from early to moderate disease, and declining in cirrhosis. A similar pattern was found in the validation cohort of NAFLD patients, where ferritin levels were highest in those with macrophage iron deposition. Multivariate analysis revealed liver iron and hepcidin levels as the major determinants of serum ferritin. Conclusions While hyperferritinaemia is associated with markers of liver injury and insulin resistance, serum hepcidin and hepatic iron are the strongest predictors of ferritin levels. These findings highlight the role of disordered iron homeostasis in the pathogenesis of NAFLD, suggesting that therapies aimed at correcting iron metabolism may be beneficial.

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Metabolic and hepatic effects of bloodletting in dysmetabolic iron overload syndrome: A randomized controlled study in 274 patients

Cited by 55 publications

References 27 publications

Systematic review and meta‐analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non‐alcoholic fatty liver disease

Systematic review and meta‐analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non‐alcoholic fatty liver disease

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease

Hepatic iron is the major determinant of serum ferritin in NAFLD patients

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