TRANSFUSIONAL IRON OVERLOAD ON YOUR PATIENTS?
T- type Ca + channels
Iron-overload cardiomyopathy, characterized by diastolic and systolic dysfunction and arrhythmias, results from genetic and acquired iron-overload conditions (1–3). The prevalence and clinical burden of secondary iron overload are increasing worldwide and are primarily because of blood transfusion in patients with hemoglobinopathies, namely thalassemia and sickle cell anemia. Voltage-gated Ca2+ chan-nels, which include the L-type (LTCC) and T-type Ca2+
channels (TTCC), are abundantly expressed in the heart and are key regulators of the excitation–contraction coupling and pacing activity in the heart (Fig. 1). In iron-overloaded conditions, non-transferrin-bound iron (NTBI) enters the cardiomyocytes through L-type Ca2+ channels and divalent-metal transporter (DMT1) and leads to iron-overload cardio-myopathy (3, 4). The use of calcium channel blockers
(CCBs) may represent a novel therapeutic tool to prevent and treat iron-overload cardiomyopathy (3).
In this issue, Kumfu et al. (5) showed that in an iron-over-loaded thalassemic murine model, the use of efonidine, a pro-posed specific blocker of TTCC, lowered mortality, prevented myocardial iron deposition and oxidative stress, and resulted in improved cardiac function. Iron-induced oxidative stress, a well-known mediator of iron-mediated tissue injury (6), and heart rate variability, a measure of the cardiac autonomic con-trol, were restored by efonidipine. Specific LTCC blockers (verapamil and nifedipine) along with the DMT blocker (ebselen) were also all effective against iron-overload cardio-myopathy in this experimental setting, while deferoxamine, a well-known iron chelator, was used as a positive control. In the normal healthy heart, TTCC are specifically confined to
SR T-Tubule
3 Na+
K+
T-Tubule
Sarcolemma
Ca2+
Fe2+
Ryanodine Receptors T-type Calcium Channel
NCX k+ Channel
SERCA 2a Phospholamban
ROS Myofilaments
Ca2+
Ca2+
Mitochondrion
Fe2+ Fe2+
2+
Na+ Channel
Na+ Fe2+ Fe2+
L-type Calcium Channel
Figure 1 Role of voltage-gated Ca2+ channels in iron transport and iron-mediated oxidative stress and the excitation–contraction coupling in a cardiomyocyte. ROS, reactive oxygen species; SERCA2a, sarcoplasmic reticulum Ca2+ATPase isoform 2; NCX, sodium–calcium exchanger; SR, sarcoplasmic reticulum.
©2012 John Wiley & Sons A/S 1
doi:10.1111/j.1600-0609.2012.01782.x European Journal of Haematology
Cardiac damage
Das SK, et al. Eur J Haematol. 2010
remains controversial as other groups show that neither MDA nor 4-HNE directly impacts HSC activa-tion.138,139 Rather, it is likely that oxidation-derived events perpetuate already activated HSCs.140,141 The precise mechanisms and pathways linking excess hepa-tocyte and Kupffer cell iron-loading, oxidant stress, and HSC activation in hemochromatosis are not fully under-stood and warrant further study.
Role of Ferritin and Transferrin in HSC Activation
The traditionally ascribed function of ferritin is the intracellular storage of iron in a nontoxic but
biolog-ically available form. Either during iron overload or in conditions of chronic inflammation, serum ferritin becomes markedly elevated and is proposed to reflect either body iron stores (as seen in hemochromatosis) or the body’s inflammatory status, respectively. The pre-cise reason or mechanisms for this elevation in serum ferritin levels are unknown, but proinflammatory cyto-kines have been shown to play a role.142 L-subunit ferritin is more tightly regulated by iron at a posttran-scriptional level than H-ferritin;143 indeed, regulation of H- and L-ferritin genes occurs under conditions of such significant iron overload that oxidative damage or inflammation may be the more relevant signals.144,145It has recently been postulated that ferritin may have
Figure 2 Potential mechanisms associated with iron overload-induced HSC activation. The deposition of iron in hepatocytes leads to cellular injury and apoptosis and/or necrosis. Phagocytosis of damaged hepatocytes by Kupffer cells is proposed to lead to the production of a variety of molecules capable of impacting on the transformation of HSC into myofibroblasts. MDA, 4-HNE, TGF-b1, IL-6, tissue ferritin, and transferrin may play a role in aspects of this activation process, derived from either hepatocytes or Kupffer cells. Tissue-derived ferritin acts as a cytokine inducing NFkB-dependent proinflammatory molecules including RANTES, iNOS, ICAM-1, IL-1b,62 and IL-6 (Ruddell and Ramm, unpublished) in HSCs. These molecules may be involved in inflammation and chemotaxis associated with wound healing, fibrogenesis, and hepatic regeneration. The role of serum ferritin and other molecules derived from extrahepatic sources via the circulatory system, such as transferrin, CCL2, CCL5, IGF, IL-6, IL-1b, TGF-b, PDGF, TNF-a, IL-10, in iron-induced hepatic fibrosis remain to be adequately investigated. L, lymphocyte; P, platelet; LPC, liver progenitor cell; HSC, hepatic stellate cell; CCL; chemokine (C-C) motif ligand; MDA, malondialdehyde; 4-HNE, 4-hydroxynonenal;
TGF, transforming growth factor; IL, interleukin; TNF, tumor necrosis factor; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; RANTES, regulated upon activation, normal T-cell expressed and secreted; ICAM-1, intracellular adhesion molecule-1; iNOS, inducible nitric oxide synthase. Dashed arrows represent potential pathways requiring further investigation.
280 SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 3 2010
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Hepatic damage
Ramm GA, et al. Semin Liver Dis. 2010
remains controversial as other groups show that neither MDA nor 4-HNE directly impacts HSC activa-tion.138,139 Rather, it is likely that oxidation-derived events perpetuate already activated HSCs.140,141 The precise mechanisms and pathways linking excess hepa-tocyte and Kupffer cell iron-loading, oxidant stress, and HSC activation in hemochromatosis are not fully under-stood and warrant further study.
Role of Ferritin and Transferrin in HSC Activation
The traditionally ascribed function of ferritin is the intracellular storage of iron in a nontoxic but
biolog-ically available form. Either during iron overload or in conditions of chronic inflammation, serum ferritin becomes markedly elevated and is proposed to reflect either body iron stores (as seen in hemochromatosis) or the body’s inflammatory status, respectively. The pre-cise reason or mechanisms for this elevation in serum ferritin levels are unknown, but proinflammatory cyto-kines have been shown to play a role.142 L-subunit ferritin is more tightly regulated by iron at a posttran-scriptional level than H-ferritin;143 indeed, regulation of H- and L-ferritin genes occurs under conditions of such significant iron overload that oxidative damage or inflammation may be the more relevant signals.144,145It has recently been postulated that ferritin may have
Figure 2 Potential mechanisms associated with iron overload-induced HSC activation. The deposition of iron in hepatocytes leads to cellular injury and apoptosis and/or necrosis. Phagocytosis of damaged hepatocytes by Kupffer cells is proposed to lead to the production of a variety of molecules capable of impacting on the transformation of HSC into myofibroblasts. MDA, 4-HNE, TGF-b1, IL-6, tissue ferritin, and transferrin may play a role in aspects of this activation process, derived from either hepatocytes or Kupffer cells. Tissue-derived ferritin acts as a cytokine inducing NFkB-dependent proinflammatory molecules including RANTES, iNOS, ICAM-1, IL-1b,62 and IL-6 (Ruddell and Ramm, unpublished) in HSCs. These molecules may be involved in inflammation and chemotaxis associated with wound healing, fibrogenesis, and hepatic regeneration. The role of serum ferritin and other molecules derived from extrahepatic sources via the circulatory system, such as transferrin, CCL2, CCL5, IGF, IL-6, IL-1b, TGF-b, PDGF, TNF-a, IL-10, in iron-induced hepatic fibrosis remain to be adequately investigated. L, lymphocyte; P, platelet; LPC, liver progenitor cell; HSC, hepatic stellate cell; CCL; chemokine (C-C) motif ligand; MDA, malondialdehyde; 4-HNE, 4-hydroxynonenal;
TGF, transforming growth factor; IL, interleukin; TNF, tumor necrosis factor; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; RANTES, regulated upon activation, normal T-cell expressed and secreted; ICAM-1, intracellular adhesion molecule-1; iNOS, inducible nitric oxide synthase. Dashed arrows represent potential pathways requiring further investigation.
280 SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 3 2010
Downloaded by: Yonsei Medical Library. Copyrighted material.