Autoimmune hemolytic anemia (AIHA) occurs when the body's immune response targets antigens on red blood cells (RBCs). This results in the destruction of red blood cells, leading to pathologically low RBC levels or anemia. 

AIHA is a rare immune disorder, impacting roughly 1 or 2 out of every 100,000 people each year. It is most common in females over the age of 40. It is important to recognize and diagnose AIHA quickly for early intervention and appropriate treatment to prevent complications or death. 

Functional medicine takes a holistic approach to AIHA. This involves identifying and addressing the root causes of diseases that can trigger this condition and bringing the body back into balance using a personalized management plan that incorporates diet, lifestyle, and integrative therapies. 

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Understanding Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia causes symptoms associated with decreased levels of red blood cells and inflammation. This can include fever, fatigue, weakness, rapid heart rate and palpitations, shortness of breath and difficulty breathing, pale skin, jaundice (yellowing skin and whites of the eyes), headaches, muscle pain, darker color urine, nausea, vomiting, diarrhea, and a sore tongue. 

Several types of AIHA are classified according to the underlying cause. Primary autoimmune hemolytic anemia is diagnosed when no apparent underlying condition can be identified. AIHA can also occur secondary to other diseases like blood cancers (such as lymphoma) or medications, including antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and some anticancer drugs.

AIHA can also occur along with certain other autoimmune conditions, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome, Hashimoto's thyroid disease, and ulcerative colitis. When AIHA occurs secondary to viral infections like Epstein-Barr virus (EBV, which causes mononucleosis), HIV, measles, mumps, rubella, varicella (the virus that causes chickenpox), atypical pneumonia, viral hepatitis, or cytomegalovirus, the anemia generally resolves once the infection is treated and cleared.

Further classification of this type of anemia is based on the type of antibodies involved. 

Warm autoimmune hemolytic anemia is the most common type of AIHA. In this condition, a type of antibody called an IgG antibody binds to red blood cells at normal body temperature. This usually leads to symptoms of anemia that occur gradually over several weeks, although sometimes symptoms can develop within days.

In cold autoimmune hemolytic anemia (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria), a different type of antibody called IgM antibodies target red blood cells when the blood is colder than the body's core temperature. Cold AIHA accounts for 10% to 20% of cases. 

Conventional Treatment Approaches for AIHA

Conventional treatments for AIHA generally involve addressing any identified underlying conditions. For example, when an infectious cause is identified, it should be treated appropriately. If AIHA is due to a medication, the specific drug may need to be switched to an alternative medication.  

When CAD is asymptomatic, treatment involves ensuring protection against exposure to cold temperatures and administering warmed blood transfusions if needed during colder weather. In cases of CAD with symptomatic anemia and/or disabling circulatory symptoms, other treatments may be added. Studies are still underway to establish the most effective course of treatment. Cytotoxic immunosuppressive drugs, such as chlorambucil or cyclophosphamide, have been studied in small case studies, and rituximab is increasingly being used due to its action of blocking the pathogenic B-cell clone, which is a pathogenic cell found in the majority of patients with CAD.

Warm AIHA is frequently treated with corticosteroids or other immunosuppressants that dampen the immune response attacking the bone marrow. Steroid treatment is effective in 70–85% of patients with warm AIHA. After the initiation of therapy, it is usually tapered over 6–12 months to avoid the side effects that can occur with long-term use. Immunosuppressants like rituximab, azathioprine, cyclophosphamide, cyclosporin, and mycophenolate mofetil are often used if there is no therapeutic response to steroids. 

Steroids increase the risk of upper gastrointestinal complications like peptic ulcers, so antacid therapy, such as a proton pump inhibitor, is commonly added, especially in those with additional risk factors. Longer-term steroid use (more than three months) also carries a risk of bone fragility and fracture. Lifestyle interventions such as avoiding smoking, limiting alcohol intake, and regular weight-bearing exercise can help prevent bone loss. Folate is sometimes also given to prevent a deficiency that can worsen anemia. 

Your spleen is home to some antibody-producing immune cells and helps remove abnormal red blood cells from your bloodstream, including those with antibodies due to AIHA. If AIHA does not respond to medications, surgery to remove the spleen (splenectomy) may be needed. 

In severe cases of AIHA, blood transfusions may be required. This can help replenish red blood cells to clinically acceptable hemoglobin values and treat anemia until other treatments become effective. To ensure a compatible transfusion, the donor blood must be carefully matched to the patient's blood type status and screened for alloantibodies.

Lastly, patients who have been diagnosed with AIHA need to be monitored for the risk of venous thromboembolism. This potentially deadly complication occurs in up to 20% to 25% of patients, especially during acute hemolysis. 

The Functional Medicine Perspective on AIHA

A functional medicine approach to AIHA addresses the underlying contributing factors and the mediators that lead to immune system dysregulation. Investigating environmental, lifestyle, and genetic factors contributing to the development of AIHA allows for a targeted approach to managing AIHA.

Understanding how various factors can contribute to immune system reactions helps us to recognize the factors contributing to autoimmunity. In most autoimmune conditions, a genetically susceptible individual experiences a loss of normal tolerance, where the immune system does not target the body's tissues. A loss of tolerance can occur with infectious processes that contribute to “superantigens." Superantigens are molecules that form from bacteria. Loss of tolerance can also occur due to a breakdown of vascular or cellular barriers and the activation of immune cells, such as macrophages and T lymphocytes, that provide costimulatory signals to the immune system. Molecular (antigenic) mimicry can occur when an antigen belonging to a microorganism, food, or toxin looks similar to a self-molecule to the immune system and triggers a cross-reactive autoimmune response. 

Gut health and the balance of microbes in the gut microbiome play critical roles in immune system function and autoimmunity that can contribute to this type of anemia. Dysbiosis impacts the system in several ways, which increases the risk of autoimmunity and AIHA. This includes increasing chronic inflammation, triggering molecular mimicry, altering epithelial barriers, and exposure to self-antigens. Imbalances in gut microbes can change the response to immune T-cells and impact systemic inflammation. This can contribute to a leaky intestinal barrier (leaky gut) that allows antigens to enter the bloodstream, where they can provoke an immune response. 

Identifying Triggers and Contributing Factors

Identifying AIHA triggers and contributing factors to anemia is essential to guide a targeted treatment plan. It is important for each individual to uncover the underlying factors contributing to immune system imbalances and inflammation. Comprehensive testing for AIHA involves an assessment of anemia and other measures of hemolytic destruction of blood cells, as well as identifying factors that may be triggering antibodies directed against red blood cells. 

Anemia can be diagnosed with a complete blood count (CBC), which measures the quantity of red blood cells and their size. It also includes an assessment of hemoglobin, the protein that carries oxygen in red blood cells, and hematocrit, which reflects the amount of space your red blood cells take up in your blood, along with platelet count. In addition, the CBC will reveal white blood cell elevations, which can be a sign of infection and inflammation.

Bilirubin can also be measured in the blood with a test like Total and Direct Bilirubin by Access Med Labs. Serum levels of unconjugated (indirect) bilirubin are released when red blood cells are destroyed in AIHA. 

Further to the CBC, a peripheral blood smear should be performed to look at a blood sample under a microscope to analyze the destruction of red blood cells.

A Coombs Test is an immunological laboratory test that can detect antibodies against red blood cells that induce hemolysis in AIHA and some other hemolytic reactions. The Direct Coombs test by Access Med Labs detects antibodies attached to red blood cells.

Using laboratory testing, screening can be done for infectious causes of secondary AIHA. The Viral Panel by Immunosciences Lab, Inc. measures antibodies against several herpesviruses that are commonly involved in inflammatory, autoimmune, and neurodegenerative disorders, including human herpesvirus 1 (HSV-1); herpes simplex virus type 2 (HSV-2), varicella zoster virus (VZV); Epstein-Barr virus (EBV); cytomegalovirus (CMV); human herpes type 6 (HHV-6); and measles (rubeola).

EBV infection can also be assessed by measuring antibodies in the blood. The Epstein-Barr Evaluation by Access Med Labs measures several antibodies to EBV to help assess active, past, or indeterminate infection. IgM antibodies to the viral capsid are elevated early in EBV infection, followed by rising IgG-viral capsid antibodies. If both IgG-VCA and EBNA antibodies are detected, this indicates past infection.

Since gut health significantly influences immune function and autoimmunity, a comprehensive stool test like Diagnostic Solutions’ GI-MAP + Zonulin test can be used to evaluate the range of microbes within the gut to identify any imbalances (dysbiosis) that may be contributing to AIHA. This testing also looks at markers of inflammation, immune function (secretory IgA), and leaky gut (zonulin) to help pinpoint factors contributing to immune dysfunction.

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Nutritional Interventions for AIHA

Anti-inflammatory diets for AIHA, such as the Mediterranean diet, help to reduce inflammation and have been shown to benefit autoimmune diseases. This way of eating emphasizes consuming various vegetables, fruit, beans, lentils, nuts, and healthy fats from olive oil and wild fish while avoiding processed foods, simple sugars, and chemical additives. 

Another option is the autoimmune paleo (AIP) diet, a version of an anti-inflammatory diet that eliminates foods with the potential to stimulate inflammation and immune dysfunction. This protocol avoids grains, legumes, and nightshades like eggplant, tomatoes, dairy, eggs, nuts and seeds, coffee, alcohol, processed foods, and refined sugar.

Specific nutrients can help support immune system balance, microbiome diversity, and red blood cell health. Nutrients, including vitamin C, vitamin D, zinc, selenium, iron, and protein, support a balanced immune response and microbiome. A diet focused on whole plant-based foods such as colorful fruits, vegetables, whole grains, and legumes provides fiber, antioxidants, and prebiotics to support immune balance. 

Nutritional support for AIHA can also help to encourage the healthy function of remaining red blood cells. Heme iron in animal-based foods like red meat, poultry, and seafood is more easily absorbed. Non-heme iron from plant-based foods like legumes, fortified cereals, spinach, kale, and dried fruits can be absorbed more effectively when consumed along with sources of vitamin C, like citrus fruits and strawberries. Certain foods contain substances that inhibit iron absorption and should be avoided or consumed away from iron sources. These include tea, coffee, calcium-rich foods, and foods high in phytates like whole grains and legumes.

In those taking steroids to treat AIHA for more than three months, ensuring adequate dietary intake of vitamin D (600-800 IU) and calcium (1000-1200 mg) can help prevent complications related to  bone fragility. Food sources of naturally occurring vitamin D include fatty fish like salmon and sardines, as well as mushrooms and egg yolks. Exposing the bare skin to natural sunlight also helps to maintain healthy vitamin D levels. Calcium can be obtained through diet by incorporating almonds, winter squash, broccoli, and leafy greens.

Lifestyle Modifications to Support Overall Health

Lifestyle changes for AIHA can also help to support a balanced immune response and improve the management of this condition. Incorporating meaningful stress reduction techniques, regular physical activity, and adequate sleep contribute to immune system regulation and reduce the severity of AIHA symptoms.

Practicing mind-body techniques can help manage stress to improve immune function and gut health. Effective strategies include meditation, mindfulness-based practices, tai chi, yoga, qigong, hypnosis, guided imagery, relaxation therapy, biofeedback, and breathing exercises.

Regular moderate exercise is also important to help manage stress, promote gut health, and reduce autoimmunity. Moderate physical activity helps decrease excess inflammation and reduces intestinal permeability, thereby reducing the risk of immune dysfunction. 

In addition, one should aim for 7-9 hours of sleep each night to support immune health and manage AIHA. Getting to bed at a regular hour and prioritizing a healthy sleep environment at a comfortable temperature without excess light and noise is essential. 

For those with cold-reactive autoimmune hemolytic anemia, it is important to avoid cold temperatures. Wear a hat, scarf, gloves, socks, and other warm clothing in cold weather and air-conditioned spaces. It can be helpful to wear gloves when removing cold food from the refrigerator or freezer.

Integrative Therapies and Supplements

Integrative therapies and supplements can be helpful in the management of AIHA in conjunction with conventional treatments. Integrative therapies for AIHA, such as acupuncture and targeted supplementation, can be personalized for each individual's unique needs.

Acupuncture is a therapy used in Traditional Chinese Medicine that involves inserting tiny needles into energy points throughout the body to help restore balance. Studies show that acupuncture can regulate inflammation and modulate TH1, TH2, and TH17 immune cells to help balance gut bacteria, enhance the intestinal barrier, and regulate inflammatory signals. This results in a more balanced gut microbiome and immune function that has been shown to benefit people with autoimmune diseases. 

Supplementation can help to balance Immune function and inflammation and reduce the risk of autoimmunity. While it is ideal to attain adequate vitamin D levels via sun exposure and foods like fatty fish, supplementation may be needed. Vitamin D helps to modulate the immune system. Deficiency of this vitamin increases the risk of autoimmune diseases like AIHA, while repletion of levels helps to reduce the risk of developing an autoimmune disease by 22%.

Another nutrient that can help reduce autoimmunity and improve gut and immune health is omega-3 fatty acids. Omega-3 polyunsaturated fatty acids help modulate the immune system and are found in fatty fish like salmon and in walnuts and algae. At doses of 1000 mg per day, the omega-3 polyunsaturated fatty acids EPA and DHA found in fish oil have been shown to decrease the risk of developing an autoimmune disease by 15%.

Supplementation with probiotics can also be helpful to support a healthy gut microbiome and reduce the risk of autoimmune and inflammatory disorders like AIHA. These beneficial microbes help to regulate the immune response and maintain a healthy intestinal barrier, which has been shown to benefit patients with multiple autoimmune diseases.

The Role of Patient Education and Empowerment

Empowering AIHA patients is a crucial step in improving their quality of life. Education helps patients better understand their condition and gives them tools to manage their health. A functional medicine approach recognizes patients' vital role in their health and supports them in navigating their health journey with AIHA.

Practitioners can evaluate patients' quality of life regularly at each visit and listen closely to each individual's concerns and questions. Allowing patients to communicate their perception of their own health status and listening to them describe the impact of AIHA on their daily lives provides valuable information and is empowering. 

Patient support and advocacy organizations can help patients understand this complicated disease and connect with resources to help guide their AIHA journey. For example, wAIHA Warriors is an organization that shares resources and provides a community of support for patients with AIHA. 

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Key Takeaways:

AIHA is an autoimmune condition affecting the red blood cells, which become damaged, causing low red blood cell counts or anemia. There are several pathogenic mechanisms involving dysregulation of the immune response that can lead to this condition. These mechanisms are triggered through a variety of factors, including genetic susceptibility, environmental and infectious exposures, and imbalances in the gut microbiome. 

Functional medicine takes a comprehensive approach to AIHA, identifying and addressing underlying causes. This allows for a personalized approach to treatment that helps patients become empowered and improves their quality of life. Comprehensive care for AIHA combines conventional medicine approaches with integrative therapies, nutrition, and lifestyle modifications.