Disrupted hepcidin regulation in HFE -associated haemochromatosis and the liver as a regulator of body iron homoeostasis

Bridle, Kim R.; Frazer, David M.; Wilkins, Sarah J.; Dixon, Jeannette L.; Purdie, David M.; Crawford, Darrell H. G.; Subramaniam, V. Nathan; Powell, Lawrie W.; Anderson, Gregory J.; Ramm, Grant A.

doi:10.1016/s0140-6736(03)12602-5

Cited by 558 publications

(426 citation statements)

References 25 publications

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“…In HFE-hemochromatosis, iron accumulates due to HFE-dependent derangement of hepcidin production (10,11). Serum hepcidin-25 levels in our Italian HFEhemochromatosis patients were low at 11.1 ± 9.2 ng/mL.…”

Section: Discussionmentioning

confidence: 61%

“…Hemochromatosis proteins act as positive regulators of hepcidin. Thus, hepcidin synthesis is at a low level in patients with HFE-hemochromatosis, which is the primary explanation for the development of iron overload in these patients (10). Venesection further decreases serum and urinary hepcidin to very low levels in patients with HFEhemochromatosis, indicating that they are still able to modulate, although inappropriately, hepcidin production in response to iron stores (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

et al. 2010

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Aim In chronic hepatitis C, iron might play an important role as a hepatotoxic co-factor. Therefore, venesection, a standard treatment for hemochromatosis, has been proposed as an alternative for patients who respond poorly to anti-viral therapy. To improve our understanding of iron-induced hepatotoxicity, we compared the responses to venesection between patients with chronic hepatitis C and those with HFEhemochromatosis. Methods Fourteen Japanese patients with chronic hepatitis C and eight Italian patients with HFEhemochromatosis underwent repeated venesection with a serum ferritin endpoint of 20 and 50 ng/mL, respectively. Serum iron indices and liver function tests were measured in pre-and post treatment blood samples from each patient. Body iron stores were calculated using the removed blood volume. Results In both patients with hepatitis and hemochromatosis, serum ferritin, aminotransferase and hepcidin 25 were reduced after venesection. The serum aminotransferase activity, but not the serum ferritin level, was predictive of effective iron removal treatment. Hepcidin regulation was set at an inappropriately low level in hemochromatosis patients (11.1 ± 9.2 ng/mL), but not so in hepatitis patients (30.7 ± 14.5 ng/mL). Inversely, the estimated body iron stores of hemochromatosis patients were 5,960 ± 2,750 mg, while those of hepatitis patients were 730 ± 560 mg. Judging from the liver enzyme reduction ratio, patients with hepatitis seemed to be more sensitive to iron hepatotoxicity than hemochromatosis patients. Conclusion Even though the threshold of iron hepatotoxicity and benefit of its removal differ between patients with chronic hepatitis C and those with HFE-hemochromatosis, venesection is a valid choice of treatment to reduce liver disease activity in both diseases.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

et al. 2010

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“…Recent data suggest that a hepcidin deficiency can be related to various forms of hemochromatosis [36]. In fact, besides the evidence that an hepcidin deficiency causes a severe iron overload in animals and is associated in humans with a severe type of juvenile hemochromatosis [34,39], it has been demonstrated that mice and humans with homozygous HFE-related hemochromatosis have inappropriately low hepatic expression and serum levels of hepcidin, implicating HFE as a possible regulator of hepcidin [40][41][42]. Moreover, the over expression of hepcidin in HFE-deficient mice prevents or delays hepatic iron accumulation [43], while the presence of heterozygous hepcidin gene mutations in patients with HFE hemochromatosis increases iron accumulation [44].…”

Section: Type 1 Hereditary Hemochromatosis (Omim 235200)mentioning

confidence: 99%

Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment

Franchini

2006

Am. J. Hematol.

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Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated timely. The elucidation of the molecular pathways of iron transport through cells and its control has led to the understanding of various genetic iron‐loading conditions. Four types of inherited iron overload have been recognized: type 1, the most common form with an autosomal recessive inheritance, is associated with mutations in the HFE gene on chromosome 6; type 2 (juvenile hemochromatosis) is an autosomal recessive disorder with causative mutations identified in the HJV gene (subtype A) on chromosome 1 and the HAMP gene (subtype B) on chromosome 19; type 3 has also an autosomal recessive inheritance with mutations in the TfR2 gene on chromosome 3; type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene on chromosome 2. In this review, the genetics, pathophysiology, diagnosis, clinical features, and management of these different types of hereditary hemochromatosis are briefly discussed. Am. J. Hematol. 81:202–209, 2006. © 2006 Wiley‐Liss, Inc.

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“…For example, reduced hepcidin level causes iron overload in hereditary haemochromatosis (HH) and iron‐loading anaemia, which is induced by ineffective erythropoiesis 4. In HH types I, II and III, mutations either in the hepcidin‐encoding gene HAMP or in genes that encode hepcidin regulators can reduce the expression of hepcidin, thereby increasing duodenal iron absorption and causing clinical iron overload 5, 6, 7. In contrast, increased hepcidin expression causes iron restriction in a variety of inflammatory conditions, including autoimmune disease, critical illness, certain types of cancers and chronic kidney disease 8.…”

Section: Introductionmentioning

confidence: 99%

Smad7 deficiency decreases iron and haemoglobin through hepcidin up‐regulation by multilayer compensatory mechanisms

Wang

et al. 2018

J Cellular Molecular Medi

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To maintain iron homoeostasis, the iron regulatory hormone hepcidin is tightly controlled by BMP‐Smad signalling pathway, but the physiological role of Smad7 in hepcidin regulation remains elusive. We generated and characterized hepatocyte‐specific Smad7 knockout mice (Smad7 Alb/Alb), which showed decreased serum iron, tissue iron, haemoglobin concentration, up‐regulated hepcidin and increased phosphor‐Smad1/5/8 levels in both isolated primary hepatocytes and liver tissues. Increased levels of hepcidin lead to reduced expression of intestinal ferroportin and mild iron deficiency anaemia. Interestingly, we found no difference in hepcidin expression or phosphor‐Smad1/5/8 levels between iron‐challenged Smad7 Alb/Alb and Smad7 flox/flox, suggesting other factors assume the role of iron‐induced hepcidin regulation in Smad7 deletion. We performed RNA‐seq to identify differentially expressed genes in the liver. Significantly up‐regulated genes were then mapped to pathways, revealing TGF‐β signalling as one of the most relevant pathways, including the up‐regulated genes Smad6, Bambi and Fst (Follistatin). We found that Smad6 and Bambi—but not Follistatin—are controlled by the iron‐BMP–Smad pathway. Overexpressing Smad6, Bambi or Follistatin in cells significantly reduced hepcidin expression. Smad7 functions as a key regulator of iron homoeostasis by negatively controlling hepcidin expression, and Smad6 and Smad7 have non‐redundant roles. Smad6, Bambi and Follistatin serve as additional inhibitors of hepcidin in the liver.

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Disrupted hepcidin regulation in HFE -associated haemochromatosis and the liver as a regulator of body iron homoeostasis

Cited by 558 publications

References 25 publications

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment

Smad7 deficiency decreases iron and haemoglobin through hepcidin up‐regulation by multilayer compensatory mechanisms

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