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Infiltrative Cardiomyopathies
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Arthur Qi, Quynh Nguyen, Haran Yogasundaram, Gavin Y. Oudit
Iron overload is defined as the accumulation of excessive iron in the body, which can be caused by both inherited and acquired etiologies.43 Importantly, the human body lacks a physiologic mechanism for the excretion of excess iron. Primary hemochromatosis is a prototypical inherited cause of iron overload and is caused by mutations in genes involved in iron metabolism.40 There are four types of hereditary hemochromatosis (Table 36.1). Type 1 is characterized by autosomal recessive mutations in the HFE gene which encodes a protein responsible for regulating hepcidin production. In type 1 hemochromatosis, increased iron absorption from the diet results in excessive iron accumulation in cells. A similar mechanism occurs in type 2 hemochromatosis, which is caused by autosomal recessive mutations in the HJV gene that codes for an iron regulatory protein named hemojuvelin. Defects in iron transporter proteins such as transferrin and ferroportin can give rise to autosomal recessive type 3 and autosomal dominant type 4 hemochromatosis, respectively.40
Systemic Diseases and the Skin
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Jana Kazandjieva, Razvigor Darlenski, Nikolai Tsankov
The different types of hereditary hemochromatosis include Type 1, classic autosomal recessive form HFE-related; Type 2a (mutations of hemojuvelin gene) and Type 2b (mutations of the hepcidin gene), autosomal recessive disease with age of onset—15–20 years; Type 3 (mutations of transferrin receptor-2 gene), autosomal recessive disease with age of onset—30–40 years; and Type 4 (mutations of the ferroprotein gene), autosomal dominant disorder with age of onset—10–80 years.
The Contribution of Iron and Transition Metal Micronutrients to Diabetes and Metabolic Disease
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Lipika Salaye, Zhenzhong Bai, Donald A. McClain
Although the most common genetic causes of the disease are mutations in the HFE protein that interacts with the TfR2 in the liver to induce hepcidin secretion, hemochromatosis also occurs with mutations in the genes for hepcidin itself (HAMP), hemojuvelin (HFE2, a coreceptor for bone morphogenic proteins that also induce hepcidin), TFR2, and ferroportin (SLC40A1), thus validating many of the pathways shown in Figure 15.1. The phenotypes of the latter forms of HH are generally more severe and present earlier in life than HFE-associated HH, which generally does not manifest until after the fifth decade and even later in females. The later onset in females is at least partially related to blood and iron loss from parturition and menstruation, although interplay of estrogen with iron metabolism may also play a role. Because of the late onset of its complications and the low penetrance of the full clinical syndrome in HFE C282Y homozygotes, the clinical significance of HH has been questioned [18,19]. Two large prospective studies, however, in which severity of disease was assessed by objective criteria including liver biopsy, including in a clinically unselected cohort, revealed the prevalence of at least one disease-related condition was 38% in males and 10% in females [20,21]. In a second study of 203 C282Y homozygotes, iron-overload related disease was found in 28.4% of men and 1.7% of women [22].
A long journey for acute kidney injury biomarkers
Published in Renal Failure, 2020
Hemojuvelin (HJV), a glycophosphatidylinositol (GPI)-linked membrane protein, is highly expressed in liver and skeletal muscles. The molecular weight of HJV is 42 kDa for the soluble form (sHJV) [49], and can be passed through glomerular filtration and reabsorbed by the renal tubules [50] Increased iron content in the kidney and urine is observed in human and animal models of AKI [51], and increased iron load can induce renal tubular cell injury [52]. There is evidence that the increased expression of the hemojuvelin-hepcidin ferroportin pathway is an intrinsic response to iron overload conditions during AKI. Therefore, urine HJV (uHJV) has the potential to be an early AKI biomarker in response to iron homeostasis during AKI, which may explain the temporal relationship between uHJV and its predictive capacity [53].
Hepcidin as a therapeutic target for anemia and inflammation associated with chronic kidney disease
Published in Expert Opinion on Therapeutic Targets, 2019
Jolanta Malyszko, Jacek S. Malyszko, Joanna Matuszkiewicz-Rowinska
Inhibition of BMps or BMPRs would lead to decreased expression of Hamp. Soluble hemojuvelin by binding to BMPs prevent their association with BMPRs [97]. It significantly inhibits BMP6 and BMP2, to a lesser extent other BMPs in cell lines [Hep3 cells) [97]. A soluble hemojuvelin-Fc fusion protein was developed and showed an ability to ameliorate anemia in the experimental model [98]. Another small molecule inhibitor, LDN-193,189, selective antagonist of activing-like kinase type 1 receptors (ALK 2 and ALK3) caused a rise in hemoglobin in the murine model [99] but not in the rat model [100,101]. Hemojuvelin is a cofactor of BMPRs, thus two monoclonal antibodies against hemojuvelin/repulsive guidance molecule C were developed to downregulate Hamp expression [101]. TNF alfa downregulate hepcidin as it suppresses hemojuvelin transcription [102]. In rheumatoid arthritis, anti-TNF alfa antibody suppresses Hamp expression [103]. As IL-6 stimulates Hamp expression through IL-6-Stat3 or other pathways [104,105], a few approaches were developed to target this pathway. Tocilizumab-neutralizing antibody to IL-6 is approved for rheumatoid arthritis and ameliorates anemia in Castleman’s disease. It decreases hepcidin and normalizes iron level [106]. AG490 inhibits Stat3 signaling and decreases hepcidin expression [107].
Effect of atorvastatin on iron metabolism regulation in patients with chronic kidney disease – a randomized double blind crossover study
Published in Renal Failure, 2018
Anna Masajtis-Zagajewska, Michal Nowicki
Hepcidin expression is regulated through the bone morphogenetic protein-hemojuvelin (BMP-HJV) signaling pathway. Hemojuvelin is a member of the repulsive guidance molecule family and appeared lately to be a key regulator of iron-dependent secretion of hepcidin. This iron-regulatory protein is mainly expressed in the liver, skeletal muscle, and heart and its production follows a specific process. The furin mRNA level is negatively regulated by iron concentrations [15,16]. The HJV produced by furin cleavage downregulates hepcidin expression by competing with hepatocyte membrane-bound mHJV for BMP binding. When not inhibited by HJV, this binding starts a cascade ending with an active protein complex that translocates into the nucleus and regulates hepcidin expression positively [17,18]. The inhibitors of 3-hydroxy-3-methy-glutaryl-co-enzyme A reductase reduce serum lipid levels and may have several other effects, including reduction of inflammation. Since statin therapy may overcome ESA hyporesponsiveness [19], it might be postulated that the beneficial effect of statins on response to ESA therapy may be mediated by a decreased release of inflammatory mediators and increased release of iron from its stores [19,20]. This concept is supported by the results of the study which shows that administration of fluvastatin in patients with end-stage kidney disease leads to a decrease of prohepcidin, a prohormone of hepcidin [21].