Trends in Endocrinology & Metabolism
ReviewIron effects versus metabolic alterations in hereditary hemochromatosis driven bone loss
Introduction
Iron is a trace element essential for life. Due to its remarkable flexibility to act as an electron donor and an acceptor, it participates in several physiological processes [1]. However, the same desirable redox potential that makes iron physiologically essential also generates toxicity in iron overload conditions. Iron accumulation resulting in iron overload can occur either due to mutations in the hepcidin/ferroportin regulatory axis or secondary to disorders of ineffective erythropoiesis and can damage organs such as the liver, heart, pancreas, gonads, and bone [2]. Thus, iron concentrations within the body must be maintained within a narrow range to avoid iron overload and iron deficiency conditions.
The liver plays critical roles in maintaining iron homeostasis. It serves as an iron storage organ to compensate for fluctuations in iron availability due to fasting or reduced dietary content. In addition, the liver orchestrates systemic iron homeostasis by sensing tissue and plasma iron levels and by producing the iron regulatory hormone hepcidin. Hepcidin is produced by hepatocytes and limits iron fluxes into the bloodstream from duodenal enterocytes and reticuloendothelial macrophages by inducing the internalization and degradation of the iron exporter ferroportin [3,4]. Deficiency of hepcidin as well as failure to modulate hepcidin expression results in systemic iron overload conditions, referred to as ‘hereditary hemochromatosis’ (HH) [5]. Mutations in the gene encoding hepcidin, HAMP, lead to juvenile hemochromatosis [6]. Besides hepcidin itself, five other genes have been implicated as causes of HH. These include iron sensory molecules such as hemochromatosis gene (HFE) [7,8], transferrin receptor 2 (TFR2) [9], hemojuvelin (HJV) [10], the molecular target of hepcidin, ferroportin (FPN), and heterozygous mutations in the BMP6 propeptide [11].
Common to all HH subtypes is the accumulation of iron in organs and tissues, which, if left untreated or poorly controlled, can lead to fatal complications such as liver cirrhosis, heart failure, or diabetes [12]. Importantly, bone is also highly susceptible to fluctuations in iron concentration. As such, osteoporosis and an increased fracture risk have been reported in a substantial number of patients with HFE-dependent HH [13]. In fact, up to one-third of patients with HFE-HH, the most common form of HH (also known as type I HH), develop osteoporosis, and 40–80% develop osteopenia [14,15]. Other forms of HH caused by mutations in TFR2 (HH type 3), FPN (HH type 4), and HJV (HH type 2A) as well as in HAMP (HH type 2B) itself produce earlier onset and more severe disease but are very rare [16]. Therefore, to date, there are no data on bone metabolism in these forms of HH. However, disease models of HH such as mice and zebrafish provided insights into the impact of HH on bone metabolism showing that, for example, hepcidin deficiency leads to bone loss via suppressed bone formation [17]. These studies confirm the tight link between iron dysregulation and osteoporosis and further show that the proteins involved in iron regulation, such as TFR2, also have direct roles in bone [18,19]. Of note, HH is also associated with various endocrine pathologies occurring due to iron overload. However, the exact contribution of direct effects of iron versus endocrine dysfunction are poorly understood. Thus, in this review, we summarize the current knowledge regarding the pathomechanisms of bone loss in patients with HH, highlight how HH proteins control iron homeostasis and bone mass, evaluate endocrine and metabolic skeletal implications of HH, and consider therapeutic consequences.
Section snippets
Regulation of iron and bone metabolism by HH proteins
Hepcidin is the central regulator of systemic iron homeostasis. Its expression is controlled by upstream activators, the hemochromatosis proteins HFE, HJV, and TFR2. As mentioned above, mutations in these genes, or in hepcidin itself, cause HH [7,9,10]. The molecular mechanism underlying hepcidin regulation by the hemochromatosis proteins is incompletely understood, but enormous progress was made in the past 20 years. The current working model is shown in Figure 1. Hepcidin production in
Bone loss in HH: associations with iron and metabolic parameters
This section focuses solely on HFE-HH, because the other HH forms are very rare and clinical data on bone metabolism are limited. Clinical manifestations of HFE-HH classically include liver disease, endocrinopathies (such as diabetes mellitus and gonadal hormone insufficiency), cardiomyopathy, changes in skin coloration, and chronic fatigue. In addition, patients have a higher propensity to develop autoimmune diseases such as arthritis [72] and are at an increased risk for infection, in
Therapeutic considerations
Hemochromatosis can be diagnosed by analyzing iron parameters, including hemoglobin, serum iron, ferritin (higher than 200 μg/L in women and 300 μg/L in men) and transferrin saturation (exceeding 45%) as well as genetic testing for HFE mutations [118]. Unfortunately, a variety of disorders cause increased ferritin levels, such as acute or chronic inflammatory disorders, cancer disease, or hepatic cytolysis (e.g., during acute or chronic liver disease or the metabolic syndrome). Thus, these
Concluding remarks
Several clinical studies indicate that bone fragility is a frequent finding in HFE-dependent HH. Data on other forms of HH are scarce due to the rarity of these diseases. Because osteoporosis and fractures correlate with the extent of iron overload in patients with HFE-HH in most studies, iron may be a critical driver of bone loss. However, the simultaneous damage to the liver and other endocrine organs may also affect bone health. Overall, HH is a multifactorial disease, and likely a
Acknowledgments
This work was supported by grants from the German Research Foundation: FerrOs FOR5146 to U.B., S.A., M.U.M., M.V.S., L.C.H., A.U.S., and M.R.).
Declaration of interests
L.C.H. received advisory board honoraria from Alexion, Amgen, Kyowa Kirin International, Pharmacosmos, Shire and UCB Pharma. M.R. received honoraria from Vifor for advisory purposes. The other authors have no interests to declare.
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