贫血与心脏病 Anemia and Heart Disease
慢性疾病性贫血-Anemia of inflammation/infection/chronic diseases
inflammation-IL6-Hepcidin-reduction of iron release (by macrophages) and iron uptake
Inflammation increases interleukin-6 production. The consequent increase in hepcidin blocks macrophage iron release as well as the intestinal absorption of iron, resulting in hypoferremia. Abbreviations: TF, transferrin; Fe, iron; DMT1, divalent metal transporter 1.
Inflammation increases interleukin-6 production. The consequent... | Download
您应该期待什么？在大多数情况下，贫血治疗需要补充铁（和/或叶酸或B12，如有需要）。如果引起贫血的根本原因是失血（除了月经），那么出血的来源也应该找到并停止。通常，这就是解决问题的全部方法。 但是，对于慢性病贫血，可能需要更广泛的治疗。一些研究表明，在严重的情况下，输血，静脉输注铁和注射促红细胞生成素可能非常有帮助。 一个警告……重要的是要记住，铁可能是一种促氧化剂，这意味着如果使用不当，它会导致体内更大的氧化应激。因此，唯一应该补充铁的人当然是月经期和孕妇。补充铁通常对儿童来说是安全的，但请事先与您的孩子的儿科医生讨论剂量。男性，绝经后的女性以及所有其他人只能在医生的照料和监督下服用铁剂。
Anemia and the Heart
By Stephen T. Sinatra, M.D., F.A.C.C., F.A.C.N., C.N.S., C.B.T.
It’s truly amazing how conditions that seemingly have nothing to do with the heart actually do impact heart health. It shows just how interconnected every single body part and system really is.
Anemia is a perfect example. Anemia is a condition that occurs when you don’t have enough red blood cells, or when your red blood cells don’t contain enough hemoglobin—the iron-rich protein that gives blood its red color. Hemoglobin helps red blood cells carry oxygen from the lungs to the rest of your organs and tissues.
Wondering if you’re anemic? Symptoms can vary. The most common is weakness, fatigue, and/or tiredness. Other symptoms of anemia may include shortness of breath, dizziness, headache, rapid heartbeat, irritability, and mental confusion.
One of the most interesting and unusual anemia symptoms is called pica. This is the habit of craving and eating unusual substances that have no nutritional value, such as ice, dirt, clay, even paper or cardboard! I’ll never forget a woman I went to medical school with who was a chronic ice chewer. I mean, she was seriously addicted to ice! We later found out she was anemic.
What Causes Anemic Symptoms?
Anemia strikes for a variety of reasons. The most common cause is iron deficiency. When the body lacks the iron needed to produce hemoglobin, anemia symptoms often kick in promptly. This usually occurs when you don’t get enough iron in the diet or, much more commonly, with blood loss. Women who have heavy menstrual periods run the risk of iron deficiency, as well as anyone who suffers from ulcers, gastritis, colon polyps, intestinal diseases, or any other condition that triggers bleeding. Anemia is also common in pregnancy, as a woman’s body needs to make additional blood to support a growing fetus.
Another form of anemia, megaloblastic anemia, results from folate or vitamin B12 deficiencies. Inadequate levels of these vitamins cause atypically large red blood cells that have a shorter-than-normal lifespan.
Other anemia causes include medical treatments such as chemotherapy and radiation, as well as the use of certain pharmaceuticals like antibiotics, seizure medications, immunosuppressants, and anticlotting drugs.
Anemia of Chronic Disease
The anemia cause that concerns me most as a cardiologist is what’s called “anemia of chronic disease.” With this form of anemia, the body does not efficiently recycle iron from blood cells, so they do not live as long as they should. The body also stops responding properly to erythropoietin, a hormone produced by the kidneys that’s responsible for boosting red blood cell production.
People with certain long-term medical conditions that involve inflammation, including some cancers and autoimmune disorders, hepatitis, kidney disease, and congestive heart failure (CHF) often become anemic. In fact, a meta-analysis of 34 studies and more than 153,000 CHF patients found that 37.2 percent of them had anemia. After a six-month follow-up, 46.8 percent of the anemic patients died compared with 29.5 percent without anemia.
Anemia also causes reduced blood flow to the kidneys, which leads to fluid retention, which places even further stress on the heart. Additionally, chronic anemia can result in left ventricular hypertrophy, the enlargement and thickening of the walls of the left ventricle—the heart’s main pumping chamber. This can worsen congestive heart failure and set up what researchers call a vicious cycle “wherein CHF causes anemia, and the anemia causes more CHF, and both damage the kidneys, worsening the anemia and the CHF further.”
So, yeah, I get concerned about anemia in patients with heart failure…and heart attack and other heart diseases. Decreased oxygen delivery leads to increased cardiac output. Simply put, this means the heart has to work much, much harder to do its job. Not only do nearly half of patients hospitalized for heart attack have anemia, people with anemia have a much higher risk of having a heart attack.
How to Treat Anemia
If you’re suffering from symptoms of anemia, see your doctor. He/she can run the appropriate tests, check for underlying health problems, and prescribe the right course of treatment.
Protect Yourself With These Heart Health Tests
What should you expect? In most cases, anemia treatment involves supplementing with iron (and/or folate or B12, if needed). If the underlying cause of anemia is blood loss (other than menstruation), then the source of the bleeding should also be located and stopped. Usually, that’s all it takes to solve the problem.
With anemia of chronic disease, though, more extensive treatment may be needed. Some research has shown that, in severe cases, blood transfusions, intravenous delivery of iron, and injections of erythropoietin can be very helpful.
One caveat…It’s important to keep in mind that iron can be a pro-oxidant, meaning it can lead to greater oxidative stress in the body if not used correctly. For this reason, the only people who should supplement with iron as a matter of course are menstruating and pregnant women. Iron supplementation is usually safe for children, but discuss dosing with your child’s pediatrician beforehand. Men, postmenopausal women, and all others should only take iron under the care and supervision of their doctors.
Khan Y and Tisman G. Pica in iron deficiency: a case series. J Med Case Reports. 2010;4:86.
Groenveld HF, Januzzi JL, et al. Anemia and mortality in heart failure patients: a systematic review and meta-analysis. J Am Coll Cardiol. 2008 Sep 2;52(10):818-27.
Silverberg DS, Wexler D, Iaina A. The role of anemia in the progression of congestive heart failure. Is there a place for erythropoietin and intravenous iron? J Nephrol. 2004 Nov-Dec;17(6):749-61.
Anemia and the Heart | Dr. Sinatra's HeartMD Institute
Causes of Anemia in Chronic Diseases
Anemia of chronic disease, also called the anemia of inflammation, is a condition that can be associated with many different underlying disorders including chronic illnesses such as cancer, certain infections, and autoimmune and inflammatory diseases such as rheumatoid arthritis or lupus. Anemia is characterized by low levels of circulating red blood cells or hemoglobin, the part of red blood cells that carries oxygen. Anemia of chronic disease is usually a mild or moderate condition. In mild cases, anemia may not be associated with any symptoms or may cause fatigue, paleness of the skin (pallor) and lightheadedness. The underlying mechanisms that cause anemia of chronic disease are complex and not fully understood.
Signs & Symptoms
Anemia of chronic disease varies in severity from one person to another. In most cases, anemia is usually mild or moderate. Affected individuals may develop a variety of symptoms such as fatigue, paleness of the skin (pallor), lightheadedness, shortness of breath, a fast heartbeat, irritability, chest pain and additional findings. These symptoms may occur in any individual who has a comparable degree of anemia. In most cases, the symptoms associated with the underlying disease usually take precedent over the mild or moderate anemia symptoms. In rare cases, anemia of chronic disease can be severe and cause more serious complications.
The exact cause of anemia of chronic disease may vary. Usually several processes are occurring concurrently. Anemia can be caused by a slight shortening of normal red blood cell survival. In addition, the production of red blood cells (erythropoiesis) or erythropoietin (a hormone that stimulates red blood cell production) may be impaired. Red blood cells carry oxygen to the body. The exact cause of anemia of chronic disease may depend upon the underlying condition. For example, cancer cells may secrete certain substances that damage or destroy immature red blood cells. In some cases, cancer cells or infectious disease may infiltrate the bone marrow, the soft spongy material found in long bones where blood cells are formed.
Researchers have also learned that individuals with anemia of chronic disease also have an imbalance in the distribution of iron in the body and as a result cannot effectively use iron to create new blood cells despite having sufficient or elevated levels of iron stored in the tissues. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low functional iron levels) or damage to affected organs (due to abnormally high iron levels in certain tissues).
Iron is needed to produce hemoglobin, the part of a red blood cell that carries oxygen. A key finding in anemia of chronic disease is increased uptake and retention of iron within certain cells, which leads to reduced amounts of functional iron that is available for the production of hemoglobin. The lack of functional iron hinders the development of hemoglobin, which, in turn, reduces the amount of oxygen delivered throughout the body (anemia).
Researchers believe that the immune system, which remains constantly active in individuals with chronic diseases, produces substances that influence the development, storage and transport of iron within the body. Cells in the immune system produce cytokines, specialized proteins that stimulate or inhibit the function of other immune system cells.
Hepcidin, a hormone produced in the liver that helps regulate the metabolism and transport of iron within the body, plays a significant role in the development of anemia of chronic disease. Researchers believe a specific cytokine known as interleukin-6 (IL-6) stimulates the production of hepcidin in most cases, although hepcidin can also be produced in response to inflammation by pathways that do not involve IL-6. Excess hepcidin causes too much iron to be trapped within cells, lowering the amount of iron available to produce hemoglobin, thereby resulting in anemia. Most researchers believe that hepcidin is a key factor influencing the development of anemia of chronic disease.
Anemia of Chronic Disease - NORD (National Organization for Rare Disorders)
Hepcidin expression is determined through transcriptional regulation by systemic iron status. However, acute or chronic inflammation also increases the expression of hepcidin, which is associated with the dysregulation of iron metabolism in pathological conditions.
Hepcidin - an overview | ScienceDirect Topics
Anemia and the Heart | Dr. Sinatra's HeartMD Institute
Hepcidin and iron homeostasis - ScienceDirect
Hepcidin has a central role in maintenance of iron homeostasis. Hepcidin synthesis is regulated at the transcriptional level by multiple stimuli. Intracellular and extracellular iron concentrations increase hepcidin transcription, as does inflammation, whereas increased erythropoietic activity suppresses hepcidin production.
Viral infection and iron metabolism
Viral infection and iron metabolism
Hal Drakesmith & Andrew Prentice
Nature Reviews Microbiology volume 6, pages541–552(2008)Cite this article
The central role of iron in fundamental processes of cellular physiology is briefly summarized. These processes must be operational for efficient viral replication, and therefore cells that are replete in iron make good homes for viruses.
Iron homeostasis in humans is outlined, and the action of the liver hormone hepcidin is described. Hepcidin maintains iron balance, and its synthesis is regulated by many proteins, one of which is HFE.
Iron overload is a risk factor for severe disease in hepatitis C virus (HCV) infection. HCV itself manipulates cellular iron transport and influences hepcidin synthesis.
In individuals infected with HIV-1, iron accumulation is associated with increased mortality. Iron accumulation in macrophages might favour virus replication, benefit secondary pathogens and lead to anaemia.
The HIV-1 protein Nef and the human cytomegalovirus (HCMV) protein US2 target HFE and therefore regulate iron transport.
New World haemorrhagic arenaviruses, canine and feline parvoviruses and mouse mammary tumour virus all use the host protein transferrin receptor 1 to gain entry to cells. In this way, these viruses infect activated, iron-acquiring cells, which can facilitate their replication.
Limiting iron availability to infected cells by iron chelators curbs the growth of HIV-1, HCMV, vaccinia virus, herpes simplex virus 1 and hepatitis B virus in vitro. In patients who are infected with HCV, iron removal ameliorates disease.
Together, these studies indicate that viruses directly manipulate iron homeostasis and that virally induced changes in iron transport are associated with altered disease states.
Fundamental cellular operations, including DNA synthesis and the generation of ATP, require iron. Viruses hijack cells in order to replicate, and efficient replication needs an iron-replete host. Some viruses selectively infect iron-acquiring cells by binding to transferrin receptor 1 during cell entry. Other viruses alter the expression of proteins involved in iron homeostasis, such as HFE and hepcidin. In HIV-1 and hepatitis C virus infections, iron overload is associated with poor prognosis and could be partly caused by the viruses themselves. Understanding how iron metabolism and viral infection interact might suggest new methods to control disease.
Viral infection and iron metabolism | Nature Reviews Microbiology
Cited by: 827
Publish Year: 2012
Author: Tomas Ganz, Elizabeta Nemeth
Hepcidin: inflammation's iron curtain
H. McGrath, Jr, P. G. Rigby
Rheumatology, Volume 43, Issue 11, November 2004, Pages 1323–1325, https://doi.org/10.1093/rheumatology/keh345
Published: 27 July 2004
Issue Section: Editorials
Rheumatologists and their patients are the beneficiaries of a recently identified peptide, hepcidin (Table 1). Isolated from human urine and plasma in the year 2000 [1, 2], hepcidin appears to be the long-sought iron-regulatory hormone responsible for the anaemia of chronic disease [3, 4]. It is more than that: it is an acute-phase reactant, responding to infection and inflammation ; it is an antimicrobial peptide that disrupts microbial membranes [1, 6]; and it provides an iron-restricted internal milieu inhospitable to microbes [7, 8].
Dynamics of iron and hepcidin regulation
Afferent: blood → Liver → Efferent: gut
Stimulation or down-regulation Hepcidin production Action on iron absorption in gut and immunity
1. Inflammation/infection ↑ ↓ intake of Fe by gut
↑ IL-6 Antibacterial in innate immunity
Sequestration of Fe in macrophages reduces serum Fe
2. Body Fe ↑ ↑ ↓ intake of Fe by gut
3. Body Fe ↓ ↓ ↑ intake of Fe by gut
Bleeding Egress of Fe out of macrophage
4. Anaemia, hypoxaemia ↓ ↑ intake of Fe by gut
5. Erythropoiesis ↑ ↓ ↑ intake of Fe by gut
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Hepcidin is a 25 amino acid, 2–3 kDa, cationic peptide that has broad antibacterial and antifungal actions . In concert with other antimicrobial peptides, known as defensins and cathelicidins , it provides a first line of defence at mucosal barriers [1, 2]. However, more germane for rheumatologists is its control of iron kinetics. Produced by hepatocytes, hepcidin inhibits the intestinal absorption [1, 10], macrophage release [3, 7] and placental passage  of iron. Hepcidin mRNA moves with the body's iron levels, increasing as they increase and decreasing as they decrease . More pertinently, hepcidin rises with infection or inflammation and falls with hypoxia or anaemia .
The anaemia of chronic disease has long confounded physicians. It is generally normocytic and normochromic, but may be hypochromic or microcytic . The low serum iron and normal-to-low iron-binding capacity, in conjunction with a high-to-normal serum ferritin level in patients with inflammatory disease, has been perplexing. Also notable has been the shortened red blood cell survival and blunted erythropoietin-induced production of red blood cells. At one time known as the anaemia of infection, it became known, after man's entry into the age of antibiotics, as the anaemia of chronic disease, and now, perhaps more aptly, it is the anaemia of inflammation.
Iron can be toxic. It catalyses the generation of reactive free radicals  and activates NF-κB, the prototypic transcription factor for genes involved in inflammation . At high levels, iron is damaging to tissues. Humans need little dietary iron, 1–2 mg a day sufficing for the average adult male . However, mammals lack a regulated pathway for iron excretion , so iron absorption has to be tightly regulated. Hepcidin acts as a negative regulator of iron absorption: USF2 knockout mice lacking hepcidin mRNA become iron-overloaded ; transgenic mice with increased hepcidin expression die at birth with severe iron deficiency ; humans with hepcidin-producing adenomas develop an iron-refractory iron deficiency anaemia ; and gene mutations affecting hepcidin cause haemochromatosis in humans  and in mouse models .
In animals and man, the anaemia of inflammation is due primarily to hepcidin-induced sequestration of iron in the macrophage . The link between inflammation/infection and liver production of hepcidin is attributed to IL-6, produced at sites of infection/inflammation . Human hepatocytes increase hepcidin mRNA in the presence of IL-6 or lipopolysaccharide and in the presence of IL-6 produced by monocytes exposed to lipopolysaccharide . Infection in one human subject reportedly increased excretion of hepcidin in the urine 100-fold . Mice respond to the inflammation generated by an injection of turpentine with a six-fold increase in hepcidin mRNA and a two-fold decrease in serum iron . Remarkably, the white bass responds to infection with Streptococcus iniae with a 4500-fold rise in hepcidin mRNA expression .
In addition to iron levels and inflammation/infection, there is another factor that affects hepcidin levels: it is anaemia. Along with hypoxia, anaemia overrides the effects of iron and inflammation/infection, reducing levels of hepcidin mRNA [4, 12]. Were this not the case, inflammation, by maintaining high hepcidin levels, would keep the haematocrit dropping. Instead, down-regulation of hepcidin mRNA expression by anaemia produces a new steady state, usually with haematocrits 3–5 points below normal.
In addition to disrupting bacterial membranes, hepcidin provides an inhospitable internal milieu for microbes that successfully enter the bloodstream. Micro-organisms need iron . Bacteria require iron for the production of the superoxide dismutase that protects them from host oxygen radicals [20, 21]. Hepcidin, by inducing macrophage sequestration of iron, robs bacteria of this element. Blood and intracellular bacteria  may weaken; biofilms may not develop . Pertinent here is the recent report of an inverse relationship between the incidence of tuberculosis and rheumatoid arthritis (RA) , raising the possibility that that the inaccessibility of iron in RA protects from tuberculosis .
Pallor, weakness and fatigue have been recognized as hallmarks of chronic disease for millennia. Anaemia obviously contributes to the pallor. Less obvious is whether the decrease in serum iron diminishes its availability to myoglobin and the enzymes catalysing the redox reactions required for the generation of energy (cytochromes) sufficiently to contribute to weakness and fatigue.
Defensins are antimicrobial peptides produced by cells of epithelial linings . Hepcidin, like defensins, is an antimicrobial peptide that kills on contact. However, because it is produced by the liver, has not been found to have chemotactic properties, and differs structurally from defensins , it will likely be classified as an acute-phase reactant .
The identification of hepcidin opens the door to therapeutic approaches for several disorders and to proscriptions regarding the use of iron. Recombinant hepcidin may be the ideal therapeutic agent for those with some forms of juvenile haemochromatosis and with the less severe but more common form of haemochromatosis caused by mutations in the HFE gene . Hepcidin-induced iron deprivation may prove helpful in preventing the development of resistant bacterial biofilms . For the anaemia of inflammation, often resistant to erythropoietin therapy , inhibitors of hepcidin, by releasing sequestered iron, could restore haemoglobin levels and conceivably correct an iron lack in myoglobin and cytochromes as well. Finally, of related interest is a recent report that moderate alcohol intake reduces levels of C-reactive protein and IL-6 , the principle chemokine for the generation of hepcidin mRNA, extrapolating to a possible ameliorative role of alcohol in both inflammation and the anaemia of inflammation.
As to proscriptions, iron supplements should be monitored, not only because the resulting increase in hepcidin can fuel antimicrobial engines unnecessarily, but because hepcidin increases macrophage iron sequestration in the synovium as elsewhere. Synovial iron has the propensity to generate oxygen free radicals that have been linked to the chronicity and erosiveness of joint disease in RA . In fact, intramuscular injections of iron have long ago been reported to cause acute flares of joint inflammation in RA . A broader phlogistic potential of iron towards the joint comes from a recent report that iron depletion by serial phlebotomies diminishes recurrences of gouty arthritis . If one adds all of the above to the reported links of iron sufficiency to colon cancer , diabetes mellitus , chronic hepatitis  and atherosclerosis , it would seem best to phase out gratuitous iron supplementation altogether.
The discovery of hepcidin provides a thread that ties together the perplexing triad of decreased serum iron, increased macrophage iron and chronic inflammation. In addition, it offers a unique opportunity for determining the effects of iron on disease, the usefulness of hepcidin inhibitors or promoters to control iron kinetics, and the proper means of iron administration. In the aggregate, these will represent a step forward in the treatment of a variety of diseases.
The authors have declared no conflicts of interest.
Hepcidin: inflammation's iron curtain | Rheumatology | Oxford Academic