In our final article in this anemia series, we will discuss anemia of chronic disease. After iron deficiency anemia (IDA), anemia of chronic disease is the second most common form of anemia worldwide. It is also one of the most common forms of anemia seen in hospitalized patients. Anemia develops in the presence of chronic disease and inflammation. Chronic disease afflicts 6https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866478/0% of American adults and is responsible for 90% of the United States' 4.1 trillion dollars in annual health care costs. (1, 4)
Functional medicine can be impactful in preventing and managing chronic disease and the resulting anemia that can ensue. By focusing on shifting the imbalances that lead to chronic disease states, integrative medicine not only plays a role in improving the quality of life in those with anemia of chronic disease but in the prevention of chronic illness so that anemia does not develop.
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What is Anemia of Chronic Disease?
Anemia of chronic disease (ACD) occurs from decreased red blood cell (RBC) production in the presence of inflammation. Contributing factors to the development of ACD include shortened red blood cell (RBC) lifespan, suppression of the RBC-stimulating hormone erythropoietin (EPO), and decreased iron availability. (1)
ACD typically falls under the classification of normocytic anemia, meaning that there is a decreased number of circulating RBCs with normal shape and size. Microcytosis (small RBCs) can develop in the later stages of anemia, partly because concurrent iron deficiency often accompanies ACD. (2)
ACD is associated with various chronic inflammatory conditions like autoimmune disease, cancer, chronic infection, and kidney disease. (1, 2)
Anemia of Chronic Disease Symptoms
ACD symptoms are primarily attributed to decreased tissue oxygenation due to reduced RBCs. Symptom severity increases as the degree of anemia worsens. Classic symptoms of anemia include (4):
- Cold hands and feet
- Dizziness
- Exercise intolerance, noted by shortness of breath and irregular heartbeat with activity
- Fatigue
- Headaches
- Pale skin
- Weakness
Risk Factors for Anemia of Chronic Disease
The presence of any chronic disease can increase the risk for developing ACD. The CDC defines chronic diseases as conditions that last at least one year, require ongoing medical care, and limit activities of daily living. Major chronic diseases responsible for death and disability in the United States include heart disease, cancer, and diabetes. Risk behaviors associated with the development of chronic disease include:
- Tobacco use and secondhand smoke exposure
- Poor nutritional status
- Diets low in fresh fruits and vegetables and high in sodium and saturated fats
- Sedentary lifestyle
- Excessive alcohol use
Conditions commonly cooccurring with ACD include:
- Autoimmune disorders, like Crohn's disease, ulcerative colitis, lupus, and rheumatoid arthritis
- Cancer, especially lymphoma
- Chronic infections
- Chronic kidney disease
- Diabetes
- Heart failure
- Obesity
This cohort study concluded that decreased glomerular filtration rate and elevated hemoglobin A1c, lab markers correlated with kidney disease and diabetes respectively, were associated with increased risk of ACD.
Labs to Diagnose Anemia of Chronic Disease
Initial workup for ACD should include the following blood work (3, 4):
- Complete blood count (CBC): a panel that measures the number and size of RBCs, white blood cells (WBCs), and platelets in the blood. Classic anemia signs are present in ACD, including low RBCs and hemoglobin. MCV, the indicator of RBC size, will be normal in normocytic states or decreased in microcytic ones. Elevated WBCs and platelets are potential findings that indicate infection and/or inflammation.
- Reticulocyte count: There will be low reticulocytes, immature RBCs, in ACD, an indicator that the bone marrow is producing fewer RBCs than usual.
- Iron Panel: This panel assesses iron status and can differentiate between ACD and IDA. Low serum iron and elevated ferritin, which increases in the presence of inflammation, are classic findings of ACD.
- C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR): biomarkers that increase in the presence of inflammation
Other causes of anemia need to be excluded before making a diagnosis of ACD. Workup and evaluation may include (3, 4):
- Serum folate to rule out folate deficiency anemia
- Serum vitamin B12 to rule out B12 deficiency anemia
- Hemoglobin electrophoresis to rule out disorders of hemoglobin synthesis (i.e., thalassemia and sickle cell anemia)
- Lactase dehydrogenase (LDH) to rule out hemolysis, the increased destruction of RBCs
- A thorough medical history to assess for anemia caused by medications or frequent blood donation
Labs to Rule Out Root Cause of Anemia of Chronic Disease
Additional evaluation should be done to identify the underlying condition causing ACD, if not already known at the time of diagnosis.
Hypothyroidism, a condition of thyroid hormone deficiency, is known to cause various anemic disorders, but most commonly ACD. A complete thyroid panel measures multiple thyroid hormones to assess for an underactive thyroid.
Chronic kidney disease (CKD) is one of the most common causes of ACD. EPO is a hormone produced by the kidneys that stimulates RBC formation by the bone marrow. In CKD, compromised EPO levels can impair sufficient RBC formation. Labs that assess kidney function include a comprehensive metabolic panel (CMP) and urinary microalbumin. (4)
A wide array of autoimmune disorders can contribute to chronic inflammation and the development of ACD. An ANA panel assesses for the presence of specific immune proteins in the blood correlated with autoimmune disease.
Hemoglobin A1c (HbA1c) is a three-month average of blood sugar and is diagnostic for diabetes.
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, must be diagnosed by colonoscopy/endoscopy and intestinal biopsy. Calprotectin, lactoferrin, and CRP can be used to support and monitor an IBD diagnosis.
If congestive heart failure is suspected, your doctor may refer you for a cardiovascular evaluation, including additional blood work, stress testing, and echocardiogram heart imaging.
Doctors may order a bone marrow biopsy to rule out certain types of cancer (3).
How is Anemia of Chronic Disease Treated?
Treatment and correction of the underlying condition will often result in the improvement of the anemia. However, when the underlying inflammation is poorly controlled, alternative conventional therapies are available to manage the anemia, including (3):
- Blood transfusion
- Erythropoietin (EPO) therapy with synthetic EPO to stimulate RBC creation
- Iron replacement with oral or intravenous iron
Functional Medicine Treatment for Anemia of Chronic Disease
Treat the Underlying Disease
Functional treatment protocols for ACD will vary depending on the underlying condition causing inflammation and anemia. Key principles in the treatment strategies of common chronic diseases include:
- Autoimmune Disease: correcting dysbiosis, implementing anti-inflammatory lifestyle practices, and supplementing with anti-inflammatory herbs
- Heart Disease: optimizing cholesterol levels and following a heart-healthy lifestyle
- Hypothyroidism: eating a gluten-free diet, supplementing with vitamins and minerals specific to thyroid function, and removing inflammatory triggers
- IBD: addressing intestinal dysbiosis, supplementing with anti-inflammatory and gut-healing herbs, and avoiding dietary triggers
- Obesity: implementing dietary modifications, stabilizing blood sugar, exercising, and optimizing sleep to encourage weight loss
- Type 2 Diabetes: intermittent fasting, limiting the intake of linoleic acid, and exercising after eating to regulate blood sugar
Herbs & Supplements
There are numerous herbs and supplements with proven anti-inflammatory properties that may be appropriate to implement when combating the inflammatory component of ACD.
- A systematic review concluded that Boswellia, or frankincense, is clinically effective and safe in managing diseases, including rheumatoid arthritis, asthma, Crohn's disease, and osteoarthritis.
- Curcumin, the anti-inflammatory compound in turmeric, is well-researched for its use in the context of many inflammatory conditions, including rheumatoid arthritis and IBD (5).
- When used in therapeutic doses, ginger improves pain scores and inflammatory biomarkers and increases the efficacy of pharmaceutical anti-inflammatories when combined (5).
- Resveratrol exhibits potent antioxidant, anti-inflammatory, and anti-cancer properties by inhibiting and modulating inflammatory pathways in the body.
- Rosemary has been confirmed in patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia to decrease CRP levels after four weeks of supplementation (5).
Lifestyle Modifications
Practicing healthy lifestyle behaviors can prevent the development of chronic disease.
- Don't smoke and avoid secondhand smoke exposure. If you smoke, talk with a doctor to develop a plan for quitting.
- Eat a healthy diet, including a variety of fresh fruits and vegetables and whole grains. Limit intake of added sugars, saturated and trans fats, and sodium.
- Be physically active. Both aerobic exercise, like running and biking, and strength training are important in maintaining health.
- Drink in moderation. Limit alcohol intake to no more than two drinks a day for men and one drink a day for women.
Summary
Anemia of chronic disease is common and is caused by underlying inflammatory conditions, leading to a decreased production of red blood cells. The diagnostic process of anemia of chronic disease includes ruling out other forms of anemia (e.g., iron deficiency anemia) and searching for an underlying causative disease if one is not already obvious. Functional integrative medicine thrives in the context of anemia of chronic disease. Functional medicine practitioners are trained in the prevention and treatment of chronic disease, understanding the underlying mechanisms behind disease pathology and how to correct contributing imbalances. The improvement and resolution of anemia of chronic disease is possible with functional testing and treatment modalities.
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