Systematic Review of the Clinical Outcomes of Iron Reduction in Hereditary Hemochromatosis

Prabhu, Anil; Cargill, Tamsin; Roberts, Nia; Ryan, John D.

doi:10.1002/hep.31405

Cited by 32 publications

(23 citation statements)

References 39 publications

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“…We constructed an HH iron overload model by injecting iron dextran into WT mice and found that redox imbalance and lipid peroxidation induced by iron overload contribute to liver damage and fibrosis [ 16 ]. Increased ROS production due to iron overload causes apoptosis and autophagy; this has been suggested to be a major pathogenic mechanism underlying HH-associated complications, including liver fibrosis and cirrhosis [ 16 , 39 ]. However, this mechanism only partly explains the clinical observation in individuals with more serious complications.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis

Feng

et al. 2021

Redox Biology

159

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Ferroptosis plays a role in several diseases such as iron overload-induced liver diseases. Manipulation of ferroptosis has been explored as a potential therapeutic strategy to treat related diseases. Numerous antioxidants have been identified to control ferroptosis but the cell-autonomous mechanisms responsible for regulating ferroptosis remain elusive. In the present study, we found that iron overload promoted ferroptosis in hepatocytes by excessively inducing HO-1 expression, which contributed to the progression of liver injury and fibrosis, accompanied by the upregulation of the FGF21 protein level in vitro and in vivo. Interestingly, both recombinant FGF21 and Fgf21 overexpression significantly protected against iron overload-induced hepatocytes mitochondria damage, liver injury and fibrosis by inhibiting ferroptosis. In contrast, the loss of FGF21 aggravated iron overload-induced ferroptosis. Notably, FGF21-induced HO-1 inhibition (via the promotion of HO-1 ubiquitination and degradation) and NRF2 activation provide a mechanistic explanation for this phenomenon. Taken together, we identified FGF21 as a novel ferroptosis suppressor. Thus, FGF21 activation may provide an effective strategy for the potential treatment of iron overload-induced ferroptosis-related diseases, such as hereditary haemochromatosis (HH).

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis

Feng

et al. 2021

Redox Biology

159

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“…In patients with liver cirrhosis or hepatocellular carcinoma, liver transplantation may be the only method of treatment [ 14 ]. Phlebotomy procedures are safe and effective, with tiredness as a main side effect [ 15 ]. The goal of the therapy is lowering serum ferritin levels below 50 ng/ml, with haemoglobin levels maintained above 11 g/dl [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

Haemochromatosis in a kidney transplant recipient: a case report

2021

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Background Iron overload is inevitably related to chronic kidney disease (CKD) treatment. Haemochromatosis leads to multiorgan damage and is associated with increased mortality. Primary haemochromatosis is the most common autosomal recessive disease in white populations. In most cases, the classic form of hereditary haemochromatosis is caused by mutations, mainly C282Y and H63D, in the haemochromatosis gene (HFE). Secondary haemochromatosis can be triggered by iron administration and blood transfusions. Haemochromatosis is rarely reported in kidney transplant recipients. Atypical factors may evoke haemochromatosis in patients without HFE mutations or other standard risk factors. Case presentation In the current study, we present a patient who started to have haemochromatosis symptoms after kidney transplantation. A 37-year-old man after kidney transplantation from a deceased donor was admitted to the hospital due to high serum ferritin levels and impaired graft function. The patient’s past medical history included arterial hypertension, embolization of both renal arteries and necrosis of the left femoral head. Glomerulonephritis was suspected as a cause of CKD; however, severe kidney failure was diagnosed, kidney biopsy was not performed, and the patient started intermittent haemodialysis. While on dialysis to treat anaemia, the patient had received erythropoietin and iron intravenously, and the maximal serum ferritin level was 2115 ng/ml. After kidney transplantation, ferritin levels started to increase rapidly, with a maximum level of 9468 ng/ml one and a half years after surgery. His genetic study showed HFE C282Y heterozygosity. Symptoms of haemochromatosis, such as skin hyperpigmentation, elevated activity of aminotransferases, impaired glucose tolerance and heart failure, were observed. Therapeutic phlebotomy was started, and 36 procedures were performed. After treatment, graft function significantly improved, most haemochromatosis symptoms resolved, and the serum ferritin level significantly decreased. Conclusions Haemochromatosis can occur in heterozygotic HFE patients after kidney transplantation. Iron administration, infections, type of immunosuppression and liver dysfunction should be considered potential triggers of haemochromatosis in this group of patients.

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“…Individuals diagnosed and treated early have a normal life expectancy (44,45), while those diagnosed after the development of cirrhosis have a decreased life expectancy, even if they are de-ironed by phlebotomy (9). Some clinical features of HH may not resolve following phlebotomy, including the arthropathy and increased risk of liver cancer, suggesting that early and irreversible changes can occur in some tissues (46,47).…”

Section: The Hemochromatosis Phenotypementioning

confidence: 99%

Revisiting hemochromatosis: genetic vs. phenotypic manifestations

Anderson¹,

Bardou-Jacquet²

2021

Ann Transl Med

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Iron overload disorders represent an important class of human diseases. Of the primary iron overload conditions, by far the most common and best studied is HFE-related hemochromatosis, which results from homozygosity for a mutation leading to the C282Y substitution in the HFE protein. This disease is characterized by reduced expression of the iron-regulatory hormone hepcidin, leading to increased dietary iron absorption and iron deposition in multiple tissues including the liver, pancreas, joints, heart and pituitary. The phenotype of HFE-related hemochromatosis is quite variable, with some individuals showing little or no evidence of increased body iron, yet others showing severe iron loading, tissue damage and clinical sequelae. The majority of genetically predisposed individuals show at least some evidence of iron loading (increased transferrin saturation and serum ferritin), but a minority show clinical symptoms and severe consequences are rare. Thus, the disorder has a high biochemical penetrance, but a low clinical prevalence. Nevertheless, it is such a common condition in Caucasian populations (1:100-200) that it remains an important clinical entity. The phenotypic variability can largely be explained by a range of environmental, genetic and physiological factors. Men are far more likely to manifest significant disease than women, with the latter losing iron through menstrual blood loss and childbirth. Other forms of blood loss, immune system influences, the amount of bioavailable iron in the diet and lifestyle factors such as high alcohol intake can also contribute to iron loading and disease expression. Polymorphisms in a range of genes have been linked to variations in body iron levels, both in the general population and in hemochromatosis. Some of the genes identified play well known roles in iron homeostasis, yet others are novel. Other factors, including both comorbidities and genetic polymorphisms, do not affect iron levels per se, but determine the propensity for tissue pathology.

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Systematic Review of the Clinical Outcomes of Iron Reduction in Hereditary Hemochromatosis

Cited by 32 publications

References 39 publications

Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis

Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis

Haemochromatosis in a kidney transplant recipient: a case report

Revisiting hemochromatosis: genetic vs. phenotypic manifestations

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