Liver hepcidin mRNA expression is inappropriately low in alcoholic patients compared with healthy controls

Costa-Matos, Luís; Batista, Paulo; Monteiro, Nuno P.; Simões, Maria João; Egas, Conceição; Pereira, Jorge; Pinho, Helena; Santos, Natália Gomes dos; Ribeiro, João; Cipriano, Maria Augusta; Henriques, Pedro; Girão, Fernando; Rodrigues, Alfredo José; Carvalho, Armando

doi:10.1097/meg.0b013e328355cfd0

Cited by 49 publications

(38 citation statements)

References 33 publications

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“…31 In the present study, %SAT predicted early mortality and also correlated with incidence of organ failure in ACLF patients, which suggests its potential as a prognostic marker in these patients. Various studies in the past have shown an inverse correlation of serum hepcidin with tissue iron in patients with CLD, 32,33 but none pertaining to ACLF. Taken together, our data highlight the importance of dysregulated iron homeostasis, which correlates with disease severity in patients with ACLF.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

et al. 2015

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Acute-on-chronic liver failure (ACLF) is an ailment with high incidence of multiorgan failure (MOF) and consequent mortality. Dysregulated iron homeostasis and macrophage dysfunction are linked to increased incidence of MOF. We investigated whether a panel of circulating iron-regulating proteins are associated with development of MOF and can predict 15-or 30-day mortality in ACLF patients. One hundred twenty patients with ACLF, 20 patients with compensated cirrhosis, and 20 healthy controls were studied. Relative protein expression profiling was performed in the derivative cohort and confirmed in the validation cohort. A panel of iron regulators and indices were determined. Multiparametric flow cytometry for quantitation of labile iron pool (LIP) was performed. Validation studies confirmed lower serum transferrin (Tf) and ceruloplasmin levels in ACLF and ACLF-MOF, compared to patients with cirrhosis and controls (P < 0.01). Serum iron and ferritin levels were markedly elevated (P < 0.001; P < 0.05) and hepcidin levels were lower (P < 0.001) in ACLF patients with MOF than those without and other groups (P < 0.001). Percentage Tf saturation (%SAT) was higher in ACLF-MOF (39.2%; P < 0.001) and correlated with poor outcome (hazard ratio: 6.970; P < 0.01). Intracellular LIP indices were significantly elevated in the subsets of circulating macrophages in ACLF-MOF, compared to other groups (P < 0.01). Whereas expression of iron-regulatory genes was markedly down-regulated, genes related to endoplasmic reticulum stress, apoptosis, and inflammation were up-regulated in ACLF patients, compared to patients with cirrhosis. Severe dysregulation of autophagy mechanisms was also observed in the former. Conclusions: Iron metabolism and transport are severely deranged in ACLF patients and more so in those with MOF. %SAT, circulating hepcidin, and LIP in macrophages correlate with disease severity and %SAT could be used for early prognostication in ACLF patients. (HEPATOLOGY 2015;61:1306-1320

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Section: Discussionmentioning

confidence: 99%

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

et al. 2015

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“…Alcohol has been shown to decrease hepcidin expression, which could lead to increased iron absorption and recycling (23). Both in vitro and human studies have described that alcohol suppressed hepcidin transcription in the liver and may protect from iron deficiency (24). However, alcohol intake was unlikely to be a major factor on hepcidin levels in this study, given that excessive alcohol consumption was an exclusion criterion for all NASH CRN studies (15, 16).…”

Section: Discussionmentioning

confidence: 99%

Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin

Siddique

Nelson

Aouizerat

et al. 2014

Clinical Gastroenterology and Hepatology

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Background & Aims Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines IL6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin and IL6 and IL1β, and other risk factors in patients with non-alcoholic fatty liver disease (NAFLD) with iron deficiency. Methods We collected data on 675 adult subjects (>18 y old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation <20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, as well as serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency. Results One third of patients (231/675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P<.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61±45 vs 81±51 ng/mL; P<.0001). Iron deficiency was significantly associated with female sex, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, Black or American Indian/Alaska Native race (P≤.018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal; P≤.0001 and 0.45 vs 0.32 for iron normal; P≤.005). Conclusion Iron deficiency is prevalent in patients with NAFLD and associated with female sex, increased body mass index, and non-white race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiological response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

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“…Each sample was reverse transcribed into cDNA using SuperScript II Reverse Transcriptase (Invitrogen). Gene expression was quantified by means of the comparative Ct method (ΔΔCt) and the relative quantification (RQ) was calculated as 2 −ΔΔCt [21–23]. Relative mRNA levels of E-CA, α -SMA, smad3, smad7, Col IV, and FN were examined and normalized to β -actin mRNA.…”

Section: Methodsmentioning

confidence: 99%

Effects of Chinese Medicine Tong xinluo on Diabetic Nephropathy via Inhibiting TGF‐β1‐Induced Epithelial‐to‐Mesenchymal Transition

Zhang

Gao

Zou

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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Diabetic nephropathy (DN) is a major cause of chronic kidney failure and characterized by interstitial and glomeruli fibrosis. Epithelial-to-mesenchymal transition (EMT) plays an important role in the pathogenesis of DN. Tong xinluo (TXL), a Chinese herbal compound, has been used in China with established therapeutic efficacy in patients with DN. To investigate the molecular mechanism of TXL improving DN, KK-Ay mice were selected as models for the evaluation of pathogenesis and treatment in DN. In vitro, TGF-β1 was used to induce EMT. Western blot (WB), immunofluorescence staining, and real-time polymerase chain reaction (RT-PCR) were applied to detect the changes of EMT markers in vivo and in vitro, respectively. Results showed the expressions of TGF-β1 and its downstream proteins smad3/p-smad3 were greatly reduced in TXL group; meantime, TXL restored the expression of smad7. As a result, the expressions of collagen IV (Col IV) and fibronectin (FN) were significantly decreased in TXL group. In vivo, 24 h-UAER (24-hour urine albumin excretion ratio) and BUN (blood urea nitrogen) were decreased and Ccr (creatinine clearance ratio) was increased in TXL group compared with DN group. In summary, the present study demonstrates that TXL successfully inhibits TGF-β1-induced epithelial-to-mesenchymal transition in DN, which may account for the therapeutic efficacy in TXL-mediated renoprotection.

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Liver hepcidin mRNA expression is inappropriately low in alcoholic patients compared with healthy controls

Abstract: Hepcidin liver expression is inappropriately low in alcoholic patients with active alcoholism and preserved hepatic function, and we conclude that this is the mechanism for alcohol consumption-associated iron overload in humans.

Cited by 49 publications

References 33 publications

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin

Effects of Chinese Medicine Tong xinluo on Diabetic Nephropathy via Inhibiting TGF‐β1‐Induced Epithelial‐to‐Mesenchymal Transition

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