HbA1c: Diagnostic Significance and Clinical Insights

Authors: Dr. Payal Bhandari, M.D., Hailey Chin

Contributors: Vivi Chador, Amer Džanković, Tejal

Hemoglobin A1C 

Hemoglobin A1c (HbA1c or A1c) estimates the percent of hemoglobin to which sugar has bonded over the prior three months. Elevated HbA1c levels result from the liver’s inability to metabolize fat, increasing the risk of diabetes, cardiovascular disease, fatty liver disease, kidney failure, dementia, blindness, and other medical conditions.

Typical Adult Range

Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.

Key Insights

HbA1c testing tracks long-term blood sugar control by showing average glucose levels over the past 8-12 weeks. It helps screen for diabetes risk, guide treatment, and monitor progress. Figure 1 shows common symptoms of abnormal HbA1c. Lowering HbA1c is key to preventing health problems from high blood sugar.

 

Figure 1: Symptoms and Signs Associated with an Abnormal HbA1c Blood Test  

 

What Is HbA1c? 

 

The HbA1c test measures the average blood sugar (glucose) attached to hemoglobin (Hb) over the past 90 days. It helps check insulin resistance and manage diabetes. Unlike a blood glucose test, it doesn’t require fasting and isn’t affected by short-term changes from meals, stress, or illness .

Hemoglobin in red blood cells carries oxygen. HbA1c forms when glucose attaches to hemoglobin. This happens over the life of a red blood cell, about 120 days, reflecting average blood sugar during that time.

 

Physiology of Hemoglobin

Origin and Formation of the Hemoglobin

Hemoglobin (Hb) is a protein in red blood cells (RBCs) that carries oxygen and gives blood its red color. It makes up 96-97% of the dry weight of RBCs, with each cell containing 640 million Hb molecules. Hb A is the most common type.

Figure 2: Hemoglobin structure. 

Each Hb molecule has four parts, made of two alpha and two beta-globin chains, and heme groups with iron at the center. Vitamin B12 and folate help oxygen bind to the iron atoms, allowing Hb to carry up to four oxygen molecules. 15 percent of hemoglobin (Hb) is formed in the mitochondria of the liver, while 85 percent occurs in the bone marrow . 

Figure 3: Hemoglobin is made inside a red blood cell. The cell’s cytoplasm makes the globin chains (alpha and beta), while the mitochondria create heme. The heme is then brought to the cytoplasm, where it joins the globin chains to form hemoglobin. 

 

Role of Hemoglobin

The main job of red blood cells (RBCs) is to carry oxygen (O2) from the lungs to tissues and remove carbon dioxide (CO2). Think of RBCs like a car, and hemoglobin (Hb) as the driver, picking up oxygen in the lungs and delivering it throughout the body.

Figure 4: Red blood cells’ (RBCs) main job is to carry oxygen (O2) to tissue and release the waste product, carbon dioxide (CO2) during exhalation. RBCs contain around 640 million hemoglobin molecules per cell. 

98 to 99 percent of O2 is carried by hemoglobin in RBCs. Since oxygen doesn’t dissolve well in blood, less than 2% is carried in the plasma. Cells use oxygen, hydrogen (from water), and carbon (from glucose) to make energy (ATP).

Figure 5: Oxygen binds to hemoglobin in red blood cells and is transported to tissue throughout the body.

In the bone marrow, red blood cells (RBCs) make hemoglobin (Hb) but lack a nucleus and mitochondria to save space for Hb and avoid using oxygen for energy. Once in the bloodstream, the Hb level stays the same throughout their lifespan.

Regulation of Hemoglobin Glycation (HbA1c)

Hemoglobin (Hb) glycation is influenced by how the body makes energy, mainly through glycolysis, which uses food to create ATP. During fasting, exercise, or insulin shortage (as in diabetes), the body breaks down fats and proteins into amino acids, lactic acid, and glycerol for energy. This process, called ketogenesis, mostly happens in the liver. The brain can’t use fat for energy, so glycerol is turned into glucose via gluconeogenesis. 

When sugars attach to hemoglobin, it can reduce oxygen delivery to tissues, causing red blood cells (RBCs) to break down faster. Higher HbA1c levels, common in diabetes, make blood thicker and worsen oxygen shortage.

Harvesting Energy After A Meal 

After eating, food is broken down, releasing glucose, fatty acids, and amino acids into the blood. Insulin helps glucose enter cells for energy, while extra carbs, fats, and proteins go to the liver for storage or conversion into energy. Waste products are detoxified by the liver.

Harvesting Energy During Short-Term Fasting and Intense Emotions

During fasting or stress, hormones like glucagon and adrenaline are released to break down stored energy. The liver and other tissues release glucose and fat, which are turned into ketones for energy.

Harvesting Energy During Low Energy States, such as Starvation and Intense Exercise

When glycogen is low, like during starvation or intense exercise, the body breaks down fat and protein into glucose for energy. This helps provide fuel when food is scarce.

 

Figure 6: Circadian rhythm genes control glucose and ketone production in the liver to manage energy. Fat, muscle, and liver cells use nutrients to make ATP. Ketones help provide energy during fasting or exercise, balance blood sugar, and improve insulin sensitivity, reducing hunger, anxiety, and stress.

Pathophysiology of Abnormal HbA1c Levels

High hemoglobin (Hb) glycation increases HbA1c levels, reducing oxygen to tissues and affecting body functions. This is often caused by poor lifestyle choices that prevent fat breakdown for energy. Low HbA1c is usually not a concern, especially with balanced cholesterol and hormones.

Figure 7 shows that abnormal HbA1c levels are linked to gut imbalances and poor blood flow. When food stays too long in the stomach, it reduces healthy bacteria, leading to nutrient deficiencies and metabolic problems. This causes undigested food and waste to enter the bloodstream, thickening blood and lowering oxygen delivery. The body compensates by making more red blood cells, and the liver stores fat instead of using it for energy.

Chronic gut imbalances reduce energy and increase reactive oxygen species (ROS), which damage red blood cells and trigger inflammation. This leads to the immune system attacking the body, causing autoimmune diseases and organ damage. Abnormal HbA1c levels are linked to inflammation, raising the risk of obesity, diabetes, hormonal issues, heart disease, autoimmune diseases, infections, and cancer.

Figure 7:  Healthy gut bacteria aid digestion, nutrient absorption, and waste removal. Dysbiosis occurs when there are fewer healthy bacteria, disrupting metabolism and boosting harmful pathogens that affect immunity . 

 

Dysbiosis (gut bacteria imbalance) disrupts the body’s ability to process nutrients and produce important molecules. This leads to undigested food and waste entering the bloodstream, thickening blood and reducing oxygen delivery. The kidneys make erythropoietin (EPO), prompting the bone marrow to produce more red blood cells (RBCs), while the liver stores fat instead of using it for energy.

Chronic dysbiosis lowers energy and increases harmful molecules called reactive oxygen species (ROS). ROS damage RBCs, cause inflammation, and lead to autoimmune diseases. White blood cells may attack the body’s own tissues. Abnormal HbA1c levels are linked to chronic inflammation, raising the risk of obesity, diabetes, hormone imbalances, heart disease, autoimmune disorders, infections, cancer, and organ damage.

 

High HbA1c Levels

High HbA1c levels lead to dehydration, shrinking red blood cells (RBCs), and reduced oxygen delivery to tissues. Chronic dehydration can lower gut bacteria diversity (dysbiosis), affecting nutrient absorption and cell production. This results in a higher concentration of RBC byproducts, like free hemoglobin and iron, in the blood. The immune system releases reactive oxygen species (ROS) to clear debris, prevent bleeding, and support wound healing.

When oxygen levels drop, heme (from hemoglobin) reduces the production of heme and hemoglobin, affecting energy production and increasing ROS and inflammation. ROS damage RBCs, causing hemolysis and releasing iron, which harms cells and raises the production of proteins like hepcidin and ferritin to regulate iron levels. High iron can damage organs and disrupt hormone production, including insulin and glucagon, affecting energy use and glucose uptake.

Figure 8: When red blood cells (RBCs) are destroyed (hemolysis), toxic byproducts like hemoglobin and iron are released into the blood. Transport proteins (haptoglobin and hemopexin) carry them to the liver and spleen, where macrophages break them down.Heme is turned into iron, which is stored or transported into the blood. It’s stored in organs like the pancreas and muscles. Heme is also converted to bilirubin in the liver and either stored in bile or excreted in stool/urine. Globulin is recycled by the liver to make new proteins.

 

Hemolysis also causes cholesterol to build up in blood vessels, leading to atherosclerosis, a process that helps repair injured vessels. High HbA1c levels are linked to excess fat and iron in organs like the liver, pancreas, and kidneys, impairing their function. This damages the ability to produce hormones, like insulin, and increases blood glucose levels, which worsens HbA1c.

 

Figure 9: Atherosclerosis causes artery thickening (tunica intima hyperplasia) and clot formation by platelets. Macrophages ingest oxidized LDL cholesterol, becoming foam cells that release inflammatory proteins and ROS. Chronic inflammation increases white blood cells and platelets, damaging cells and microbiota, reducing organ function, and raising the risk of health issues.

 

Rising HbA1c levels are related to:

  • Increased undigested food and waste in the bloodstream, damaging RBCs and accelerating their destruction.

  • Dysbiosis, which causes nutrient deficiencies and affects RBC production.

  • Excess fat and iron stores reducing energy production.

  • Increased ROS that damage tissues and mutate genes.

  • Overactive white blood cells (WBCs) and platelets that focus on tissue repair instead of fighting infections or tumors.

  • Chronic stress response overstimulation, leading to hormonal imbalances and increased risk for autoimmune endocrine disorders like Hashimoto’s disease, Graves’ disease, and diabetes.

 

Figure 10: Rising HbA1c is closely linked to excess concentration of proinflammatory proteins, oxidized cholesterol, and reactive oxygen species in the circulation damaging tissues, thereby forcing white blood cells (leukocytes) and platelets (thrombocytes) to work with pathogens, and tumor cells to repair injuries and clear out tissue debris. 

Tumor cells and pathogens are recruited by platelets to ingest free hemin and iron, respectively, enabling them to reproduce and migrate (1). Neutrophils focus on stabilizing the integrity and function of the blood vessel by releasing proinflammatory proteins (2)40 and tumor cell-induced platelet activation (3) and formation of new blood vessels (angiogenesis) (4). Natural killer (NK) cells are prevented from ingesting and destroying tumor cells and pathogens (5) . Thus, the cytokines released enable pathogens to produce toxins that damage red blood cell membranes, steal nutrients (like iron and oxygen) from other organs, and induce infections and tumor growth (6). 

These conditions can cause symptoms like irregular periods, infertility, fatigue, poor bone health, skin issues, and more. For example, weakened collagen due to low blood flow can cause bone density loss, dry skin, and slow healing.

Low HbA1c Levels

Abnormally low HbA1c levels (<4.0%) can indicate problems like shortened red blood cell (RBC) lifespan, increased RBC destruction, and reduced energy production, which can raise the risk of illness and death. Low HbA1c may appear similar to high HbA1c, and younger RBCs, which are larger, can affect HbA1c and RBC distribution width (RDW). An abnormal RDW is linked to higher risks of illness, death, and inflammation.

Low HbA1c can be caused by several factors:

  1. Overuse of blood sugar-lowering drugs: These drugs can cause low blood sugar (hypoglycemia) and reduce HbA1c levels, affecting hormones that control metabolism and oxygen delivery, leading to decreased energy production and increased free radicals (ROS).

  2. Antibiotic use: Frequent antibiotics can lower gut bacteria diversity (dysbiosis), leading to nutrient deficiencies that reduce RBC and hemoglobin production, lowering HbA1c.

  3. Dehydration: Dehydration increases blood ion concentration, causing RBCs to shrink, reducing oxygen delivery to cells (hypoxia). This speeds up RBC destruction and lowers HbA1c levels.

Figure 11: Effects of water osmosis on the integrity and functioning of blood cells. Water osmosis is the transportation of water throughout a cell that is determined by the cell’s solute concentration. Hypotonic cells have a higher solute concentration inside the cell than outside of the cell causing more water to be transported inside of the cell. Isotonic cells have the same solute concentration inside the cell and outside the cell causing water to be transported into and out from the cell equally. Hypertonic cells have less solute concentration inside the cell causing the cell to transport water out of the cell.   

 

Other causes of fluid loss that lower HbA1c include:

  • Slow blood loss, often from heavy periods or conditions like anemia and chronic digestive disorders (e.g., inflammatory bowel disease).

  • Excessive blood loss during surgery or trauma.

  • Frequent blood donations or blood draws.

These factors can lower HbA1c, reducing energy production and increasing glucose synthesis and ROS production.

 

Prevalence and Statistics of Abnormal HbA1c Levels

Both high and low HbA1c levels signal health issues, mostly linked to diabetes. High HbA1c (above 5.7%) and low HbA1c (below 4.0%) are influenced by poor diet, lack of exercise, obesity, and medication. Diabetes affects 38.4 million people worldwide, with 10.5% of adults having the disease, half of whom are unaware. Diabetes increases the risk of heart attack, stroke, and kidney disease. The number of people with diabetes is expected to rise to 643 million by 2030 and 783 million by 2045 . 

High HbA1c levels usually indicate diabetes and a higher risk of heart disease, stroke, and kidney damage. Type 2 diabetes is increasing in American Indian youth due to poor blood sugar control, lack of exercise, and bad nutrition. 67

Low HbA1c levels can signal hypoglycemia or issues with red blood cells. While less common, low levels increase the risk of death, liver disease, and bleeding. In the U.S., people with low HbA1c have nearly three times the risk of death compared to those with normal levels 46. 

Conclusion

Interpreting HbA1c tests requires considering factors like age, lifestyle, medications, and conditions that affect digestion and metabolism. Other tests may help identify the cause of abnormal results related to glucose, red blood cells, nutrient absorption, and organ function.

To manage abnormal HbA1c levels, lifestyle changes, medication adjustments, and stress reduction are important. If these don’t work, medications may be needed to prevent complications.

Poor diet, sleep issues, and stress can reduce blood flow to organs, causing nutrient deficiencies and lowering HbA1c levels temporarily. A healthy, plant-based diet, regular exercise, stress management, and 7-9 hours of sleep for adults and 10-12 hours for children are crucial for balancing HbA1c and blood glucose levels.


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