Leukemia Overview: Symptoms, Signs, Treatment and Causes

Exhausted? Irritable? It Could Be Undiagnosed Iron Deficiency

About three years ago, Soumya Rangarajan struggled day after day with exhaustion, headaches, and heart palpitations. As a front-line hospital doctor during the COVID-19 pandemic, she first attributed her symptoms to the demands of an unprecedented health care crisis.

But a social media post got Rangarajan thinking about the possibility that she might actually be the victim of something more mundane: an iron deficiency. She requested a blood test from her doctor, and the results determined she had anemia, a condition caused by lower-than-normal levels of iron in the blood.

It was the first step toward relief, recalled Rangarajan, who is a geriatrician at the University of Michigan. Her symptoms, she added, had made it so she "had difficulty getting through a full week at work."

Although estimates vary, some research suggests that about a third of women of reproductive age in the United States may not get enough iron, which helps support various functions in the body. But despite the high risks, iron deficiency isn't routinely screened for during annual health examinations.

"Women are only tested if they present to a health care provider and are having symptoms," said Angela Weyand, a pediatric hematologist at the University of Michigan Medical School.

And while the American College of Obstetricians and Gynecologists does recommend routinely screening pregnant people for anemia — a medical condition that can be caused by iron deficiency and results in the body having too few healthy red blood cells — providers likely miss many patients who are iron deficient but not anemic, Weyand said, since it requires other testing.

Meanwhile, the U.S. Preventive Services Task Force, which makes recommendations about clinical preventive services, recently reviewed studies on iron deficiency screening and supplementation practices for asymptomatic pregnant people. On Aug. 20, it concluded that there was insufficient evidence to recommend routine screenings, since the existing data was unclear about whether screening for an iron deficiency absent symptoms made a significant difference.

But many clinicians disagree. And the ambiguous nature of iron deficiency signs — which can include lethargy, irritability, and pale skin — coupled with the lack of specific recommendations for nonpregnant women, means the condition can be easily overlooked, Weyand said. Doctors might simply suggest to tired women that they should get more sleep, for example.

For Margaret Ragni, who recently retired as a hematologist, it was fairly common for female patients to come in with symptoms that pointed to low levels of iron in the body.

"Iron deficiency is associated with a really poor quality of life," said Ragni, also an emeritus professor of clinical translation research at the University of Pittsburgh. Annual screenings could go a long way toward offering relief: "These poor women really could feel so much better."

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Iron supplements can come with difficult side effects, and evidence is lacking to show whether prenatal iron supplementation helps with pregnancy. Health effects of low iron and anemia

Iron is a vital component of a protein in red blood cells, hemoglobin, which helps carry oxygen to every part of the body. The mineral is also essential for a number of various other cellular functions, including energy production and maintenance of healthy skin, hair, and nails.

The body can store some iron temporarily in the form of a protein called ferritin, but if the levels dip too low for too long, so does the hemoglobin in red blood cells, resulting in anemia. But even before anemia, low iron levels can cause health problems.

In addition to physical symptoms such as lightheadedness and shortness of breath, women with iron deficiency can struggle with anxiety, depression, and restless leg syndrome, Weyand said. Iron deficiency has also been linked to heart failure, hearing loss, and pica — a craving for substances like ice, dirt, or clay.

"People can have hair loss and nail changes," she said. "They can have decreased cognitive abilities, which is hard to tease out."

Many physicians "think of iron deficiency in terms of anemia, but that's the last manifestation of iron deficiency," Weyand said. "And we know iron is important for a lot of other things."

Pregnancy increases need for iron

The need for iron especially increases during pregnancy, when people are even more vulnerable to anemia, said Michael Georgieff, a pediatrics professor and co-director of the Masonic Institute for the Developing Brain at the University of Minnesota.

But even when a growing fetus demands more iron intake, women may not always be screened for iron deficiency. Georgieff recalled that three years ago, he accompanied his pregnant daughter to see her obstetrician and was surprised to learn that her blood wouldn't be tested for iron deficiency. When he asked why, he was told that only people who reported symptoms were screened.

"Pregnancy itself is essentially an iron-deficient state," he said. "In other words, the iron requirements of the mom go up dramatically during pregnancy. And if you don't screen and supplement, it's very hard to keep up with her iron status."

Moreover, when pregnant women develop anemia, they likely will have difficult pregnancies, Georgieff said. "The consequences are more premature births, more low birth weight babies. And those babies are not loaded with enough iron for their needs once they are out."

During pregnancy, the fetus depends on the maternal iron it gets through the placenta, a temporary organ that also provides nourishment and oxygen. If mothers-to-be have low iron or anemia, it can affect newborn development. There's evidence that if a woman is iron deficient when she conceives, or during the first trimester, it may pose a higher risk for the baby's brain development.

Anemia during pregnancy has long been associated with greater risks of delivering premature babies and possible health conditions for mothers, including preeclampsia.

But research suggests that even though the condition can have an impact, it is still unclear whether iron therapy can adequately reduce risks. And while many experts agree on the need to treat iron-deficiency anemia, there is no consensus for treatment of iron depletion not associated with anemia.

Ragni said she made it a point to screen patients for depleted iron to catch it before anemia develops. But, she said, recommendations from institutions such as the U.S. Preventive Services Task Force could prompt more U.S. Providers to screen.

"For women of reproductive age, whether they're pregnant or not, it's really critical to test," Ragni said. "There should be a standard test for these women."

Debate over measuring iron deficiency

A major reason for iron deficiency among nonpregnant women is menstrual bleeding, which is why they're at comparatively higher risk to men. "Women who have excess blood loss are really at an even higher risk," said Ragni.

The World Health Organization has estimated that, worldwide, about 30% of women between 15 and 49 years old were anemic in 2019, with iron deficiency estimated to be responsible for about half of cases.

And some research suggests that vulnerability to iron deficiency can start at a young age. A 2023 study that Weyand co-authored found that the overall prevalence of iron deficiency among women and girls aged 12 to 22 was more than 38%; the prevalence of anemia was about 6%. But that rate changes depending on how iron deficiency is defined.

To determine someone's iron count, labs look at the concentration of ferritin — the protein that stores iron — in their blood. A common threshold established by the World Health Organization says that anything under 15 micrograms of ferritin per liter of blood is iron deficient. When Weyand's team used that threshold, they found that 17% of participants were iron deficient. But when they upped the threshold cutoff to 50 micrograms per liter, the number of iron-deficient participants climbed to nearly 78%.

Weyand and other researchers say the results reflect a need for a higher threshold for women of 50 micrograms per liter for ferritin, since some studies suggest that such a cutoff is often consistent with iron deficiency. But there's a lack of consensus about which cutoff is most accurate to indicate iron deficiency; other research, for example, suggests 30 micrograms per liter is an effective cutoff to use.

Still, researchers like Weyand call for raising the thresholds to avoid false negative results that would keep people with iron deficiency from being diagnosed and treated. This would, she said "capture patients who otherwise have been ignored and dismissed or told their symptoms were due to some other issue."

Treating low iron

Weyand became an advocate for people who struggle with iron deficiency after seeing many patients with heavy menstrual bleeding and iron depletion. Most had never been screened or received treatment.

While iron deficiency in nonpregnant women is primarily associated with menstruation, other risk factors include diets that don't have enough iron, as well as gut disorders, like celiac disease, that cause poor iron absorption. There's also evidence that women in low-income communities are at higher risk of iron deficiency because of a lack of access to health care and iron-rich foods like meat, dark leafy vegetables, salmon, and tofu.

Iron deficiency is an easily treatable condition with iron supplements, Weyand said, but "it's difficult to treat if you don't know it's there."

After her anemia diagnosis, Rangarajan said she started taking iron tablets daily, but cut back to three times a week for a few months. She found it hard to cope with the side effects, which included stomach cramps, nausea, and constipation.

Rangarajan, 39, eventually urged her primary care physician to switch her treatment to intravenous iron supplements. After waiting for several months for approval from her medical insurance, Rangarajan got her first infusions in March. The effect took hold within a week.

"The headaches were gone; I didn't notice any palpitations anymore; my energy levels were up," she said. "So I definitely noticed a significant difference."

In fact, it was one of Weyand's social media posts that prompted Rangarajan to get tested for iron deficiency. Weyand often advocates on her online platforms for attention to iron deficiency in people and hears from many working women about how diagnosis and treatment of iron deficiency had finally ended "horrible" symptoms that sometimes lasted for decades. "We are vastly undertreating iron deficiency currently," she said.

After menopause, when women stop bleeding, they need much less iron. Requirements for the nutrient drop from a daily average iron intake of about 18 mg to around 8 mg.

"What's hard is that the vast majority of these women aren't diagnosed while they are menstruating, and so, going into menopause they probably are low," Weyand said. "And depending on how low they are, it would dictate how long it would take them to replenish once they stop bleeding."

Iron deficiency is rare in men — estimated to affect about 2% of U.S. Men — but when it develops, similarly to menopausal women, it can signal an underlying condition such as an ulcer or cancer. As Weyand put it: "It's more of a red flag in terms of figuring out why they're iron deficient."

A call for more screening and research

Iron deficiency is a significant health problem not just in the U.S., but worldwide. The International Federation of Gynecology and Obstetrics, which promotes women's health globally, issued recommendations in 2023 to regularly screen all menstruating women and girls for iron deficiency — ideally, throughout their life.

Weyand said she hopes the recommendations and more research into the health benefits of iron deficiency screening will help increase awareness among U.S. Health providers of the need to screen for iron deficiency. "We screen for lots of things that are less common than this," she said.

Meanwhile, the findings that the U.S. Preventive Services Task Force didn't sit well with Georgieff, whose research at the University of Minnesota focuses on the effect of iron on fetal brain development. Health care providers are not generally screening for iron, he said, and the task force's decision does nothing to promote change.

While the task force acknowledged that pregnant people are at high risk of developing iron deficiency and iron deficiency anemia, it concluded that there's a lack of evidence on the effectiveness of screening pregnant people who show no signs or symptoms.

The latest task force review included 17 studies on the impact of routine iron supplementation on pregnant people. They found that compared with placebo, prenatal iron supplementation resulted in no significant differences in maternal quality of life or conditions such as gestational diabetes, cesarean deliveries, or maternal hemorrhage.

None of the studies examined the benefits or harms of screening for iron deficiency and iron deficiency anemia during pregnancy. The volunteer panel issued an I statement, which stands for "Insufficient Evidence to Make a Recommendation," and is given when the evidence is either not available, or when it is poor or conflicting.

In 2015, the group also reached a similar conclusion after assessing existing evidence at that time regarding iron deficiency anemia in pregnant people.

More research is needed to effectively assess the potential health impact of iron screening and supplementation for asymptomatic pregnant people, said Esa Davis, a task force member and associate vice president for community health at the University of Maryland.

"We need studies that are done to show us the benefit or the harm of screening for both iron deficiency and iron deficiency anemia," she said, "and studies that show us the benefits and the harm of supplementing in this group as well."

Weyand said she hopes ongoing research on iron deficiency in women will boost the chances that the task force and other groups will take up the issue of regular screening again — both for pregnant and non-pregnant people. "Hopefully, it will lead to meaningful change," she said.

Having felt the debilitating effects of iron deficiency and anemia, Rangarajan said she knows firsthand how crucial screening can be for diagnosis and effective treatment.

"I feel like my energy is so much better. I feel like my performance at work has improved tremendously with IV iron because I don't feel so fatigued even at a very busy stretch," she said. "I feel like I have this strength that I had when I was in my 20s."

This article was originally published on Undark. Find the original article here.

Lourdes Medrano is a journalist based in Southern Arizona and a senior contributor at Undark. Her reporting often focuses on matters relevant to both sides of the U.S.-Mexico border, including environmental issues.

Copyright 2024 Undark Magazine

Exploring The Impact Of Iron Overload On Mitochondrial DNA In β-thalassemia

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Saturation of TfR1 leads to the dissociation of Hfe and the binding of the alter to the TfR2, which in turn influences the binding of BMP6 to its receptors on the membrane. Increased liver iron concentration induces the expression of the BMP6 gene, forming BMP6 proteins, which bind to the BMP receptors (ALK2). When bound to BMP6, the receptors recruit SMAD proteins and phosphorylation of SMAD1/5/8-SMAD4 complex mobilizes to the nucleus, activating the expression of hepcidin. Inflammatory signals via IL-6 through the JAK-STAT cascade induce the expression of the Hepcidin gene (HAMP). Higher EPO and HIF lead to the secretion of ERFE from erythroid precursor cells, which attenuates the BMP6 signaling cascade via GDF15/TWSG1. In the absence of BMP6, TMPRSS6 binds to ALK2, inhibiting the hepcidin signaling cascade. BMP6, bone morphogenic protein 6; EPO, erythropoietin; ERFE, erythroferrone; Erk, extracellular signal-regulated kinase; GDF15, growth differentiation factor15, HAMP, hepcidin antimicrobial peptide; Hfe, hemochromatosis gene; HIF, hypoxia-induced factor; IL-6, interleukin 6; JAK-STAT, Janus kinase/signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; sHJV, soluble hemojuvelin ; SMAD, mothers against decapentaplegic; TfR1/2, Transferrin receptor; TMPRSS6, transmembrane serine protease 6; TWSG1, twisted gastrulation factor1.

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Credit: Akila Prashant

β-Thalassemia is a genetic disorder characterized by reduced or absent synthesis of the beta chains of hemoglobin, leading to ineffective erythropoiesis and severe anemia. Patients with transfusion-dependent β-thalassemia (TDT) require regular blood transfusions to maintain adequate hemoglobin levels. Non-transfusion-dependent thalassemia (NTDT) patients manage their anemia without regular transfusions but still experience significant health complications. Iron overload is a common and severe complication in both TDT and NTDT patients due to increased intestinal iron absorption and regular transfusions. The excess iron accumulates in vital organs, including the liver, heart, and endocrine glands, causing significant morbidity and mortality. This review explores the mechanisms of iron overload in β-thalassemia, current diagnostic and monitoring techniques, and advances in management strategies.

Mechanisms of Iron Overload

In β-thalassemia, iron overload occurs through two primary mechanisms: transfusional iron overload in TDT patients and increased gastrointestinal iron absorption in NTDT patients due to ineffective erythropoiesis and low hepcidin levels. Hepcidin, a liver-derived hormone, regulates iron homeostasis by inhibiting intestinal iron absorption and iron release from macrophages. In β-thalassemia, hepcidin levels are inappropriately low, leading to excessive iron absorption. This dysregulation results in systemic iron overload. The iron overload leads to the production of reactive oxygen species (ROS) through iron-mediated Fenton reactions, contributing to oxidative stress and tissue damage. Chronic iron overload is particularly detrimental to the liver, heart, and endocrine organs, leading to fibrosis, cardiomyopathy, and endocrine dysfunctions, respectively.

Diagnosis and Monitoring

Diagnosing iron overload involves several parameters, with serum ferritin levels being a primary indicator. Elevated serum ferritin levels, typically above 300 ng/ml in males and 150–200 ng/ml in females, signal excess iron accumulation. However, inflammation, infection, and liver disorders can affect ferritin levels, necessitating the use of additional markers such as total iron binding capacity, serum transferrin saturation, and non-transferrin-bound iron (NTBI). Magnetic resonance imaging (MRI) has replaced liver biopsy for non-invasive quantification of hepatic iron overload and can also assess iron accumulation in the heart and other organs. T2* MRI is particularly useful for evaluating cardiac iron overload and guiding chelation therapy adjustments. Liver iron concentration (LIC) measurement through R2 and R2* MRI techniques provides a reliable assessment of hepatic iron burden.

Management Strategies

The primary treatment for iron overload is chelation therapy, which involves the use of agents such as deferoxamine, deferiprone, and deferasirox to bind excess iron and facilitate its excretion. Chelation therapy's efficacy depends on patient adherence, which can be affected by side effects and cost. Deferoxamine, administered via subcutaneous or intravenous infusion, is effective but burdensome for patients. Oral chelators such as deferiprone and deferasirox offer more convenience, improving compliance. Emerging therapies aim to enhance chelation efficiency and reduce side effects. These include the development of new chelators, combination therapies, and the use of plant extract derivatives with antioxidant properties. Combination therapy, using deferiprone and deferoxamine, has shown synergistic effects, improving iron removal and reducing toxicity.

Future Perspectives

Research is focused on understanding the molecular mechanisms underlying iron overload and developing targeted therapies. Advances in genetic and molecular screening have improved our understanding of genotype-phenotype correlations in thalassemia. Techniques such as next-generation sequencing (NGS) enable the identification of mutations in genes regulating iron metabolism. Innovations in gene editing, such as CRISPR-Cas9, hold promise for correcting genetic defects responsible for iron overload. Additionally, nanoparticle-based delivery systems offer potential for targeted therapy, reducing systemic toxicity and improving therapeutic outcomes. Hepcidin mimetics and modulators are also being investigated to restore hepcidin levels and regulate iron absorption effectively.

Conclusions

Iron overload remains a significant challenge in the management of β-thalassemia. Early diagnosis and regular monitoring are crucial for preventing organ damage. While chelation therapy is the cornerstone of treatment, its limitations necessitate the exploration of novel therapeutic strategies. Advances in molecular genetics and targeted therapies offer hope for more effective management of iron overload in β-thalassemia patients. Personalized treatment approaches, informed by genetic and molecular profiling, are essential for optimizing patient outcomes. Continued research and clinical trials are vital to developing safer, more effective treatments and improving the quality of life for β-thalassemia patients worldwide.

 

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The study was recently published in the Gene Expression.

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Article Title

Exploring the Impact of Iron Overload on Mitochondrial DNA in β-Thalassemia: A Comprehensive Review

Article Publication Date

15-Apr-2024

What Is MCH And What Do High And Low Values Mean?

A doctor can help you determine whether you need treatment. The treatments for abnormally high MCH levels depend on how high your levels are and the underlying cause.

Treatment for anemias caused by B-12 or folate deficiencies are commonly treated by supplements of these vitamins to further boost your B-12 and folate levels or, if absorption is a problem, prescribe B-12 injections.

Your doctor may also recommend lifestyle changes and adding foods rich in vitamin B-12 and folate to your diet.

Management of high MCH due to hyperthyroidism, liver disease, or lung disease typically includes managing the underlying condition.

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