Hemoglobin C

Hemoglobin is an essential iron-containing protein in red blood cells that transports oxygen from the lungs to the body and returns carbon dioxide for exhalation. 

Beyond oxygen delivery, hemoglobin helps regulate blood pH, supports vascular function, and plays key roles in immune defense and red blood cell stability.

Hemoglobin: Definition and Function

Hemoglobin (Hb) is a protein found in red blood cells that carries oxygen from the lungs to tissues and returns carbon dioxide to the lungs for exhalation. 

Each hemoglobin molecule consists of four globin chains and four heme groups, with each heme containing an iron atom that binds oxygen. 

Function

Hemoglobin plays several critical roles in the body. 

It enables oxygen transport, facilitates carbon dioxide exchange, helps buffer blood pH by binding hydrogen ions, and supports blood flow by releasing nitric oxide for vasodilation. 

Through the Bohr effect, hemoglobin adjusts oxygen binding based on carbon dioxide levels and pH: releasing oxygen in acidic, high-CO₂ tissues and binding it more readily in the lungs. 

Hemoglobin also contributes to immune defense by generating reactive oxygen and nitrogen species, regulating vascular function, and activating immune signaling pathways during infection and inflammation. 

In hemolysis, it can promote oxidative damage by scavenging nitric oxide and generating reactive radicals. 

Finally, hemoglobin turnover recycles iron and supports osmotic balance in blood volume regulation.

Hemoglobin Types

The following types of hemoglobin may be present in humans: 

Hemoglobin A1 (HbA1)

This is the primary type of hemoglobin found in healthy adults. It makes up about 95–98% of the total hemoglobin in the blood. 

HbA1 is made of two alpha and two beta chains and carries oxygen through the body.

Hemoglobin A2 (HbA2)

A normal but minor form of adult hemoglobin, it accounts for about 2–3% of total hemoglobin. 

HbA2 is made of two alpha and two delta chains. Higher levels can be a sign of a condition called beta-thalassemia.

Hemoglobin F (HbF)

Also called fetal hemoglobin, this type is found in unborn babies and newborns. It's made of two alpha and two gamma chains. HbF has a strong ability to hold onto oxygen, which helps deliver oxygen from the mother to the baby. 

Most people's HbF levels drop after infancy, but if they remain high in adults, it may indicate a blood disorder like thalassemia.

Hemoglobin E (HbE)

Hemoglobin E (HbE) is a common structural variant of hemoglobin found primarily in Southeast Asia. 

Individuals with one copy of the HbE gene (heterozygotes) may have mild, hypochromic anemia, while those with two copies (homozygotes) typically have mild anemia that can worsen with infections or certain medications; when combined with beta-thalassemia, it can lead to more serious disease.

Hemoglobin S (HbS)

This is an abnormal type of hemoglobin caused by a change in the beta-globin gene. It causes red blood cells to become stiff and sickle-shaped, which can block blood flow and lead to pain and organ damage.

People with two copies of the HbS gene have sickle cell anemia. This form is most common in people of African ancestry.

Hemoglobin C (HbC)

Hemoglobin C is another abnormal type of hemoglobin caused by a different mutation in the beta-globin gene.

There are 3 manifestations of hemoglobin C in human health and disease: 

• Hemoglobin C Trait (HbAC): occurs when an individual inherits one normal β-globin gene (A) and one hemoglobin C gene (C). Carriers are typically asymptomatic but can transmit the HbC allele to their offspring.
• Hemoglobin C Disease (HbCC): results from inheritance of two HbC alleles. Affected individuals usually experience mild chronic hemolytic anemia.
• Hemoglobin SC Disease (HbSC): this arises from the inheritance of one HbC allele and one HbS allele (the variant associated with sickle cell anemia), which presents with variable severity; clinical symptoms are generally less severe than in sickle cell anemia (HbSS), but more pronounced than in HbCC disease.

People with two HbC genes (HbCC) may have mild anemia because their red blood cells don’t live as long. 

Hemoglobin C Disease

Hemoglobin C disease (HbCC) is a mild, inherited blood disorder caused by a change in the beta-globin gene. 

In this condition, one building block in the hemoglobin protein—glutamate—is replaced by lysine. This makes the hemoglobin less soluble and causes crystals to form inside red blood cells, leading to mild, long-term breakdown of these cells (chronic hemolysis).

People with HbC trait (HbAC) have only one copy of the gene and usually have no symptoms. 

Those with HbCC may have mild anemia, tiredness, pale skin, an enlarged spleen, or yellowing of the skin or eyes (jaundice). Some may also develop gallstones over time. 

Hemoglobin C does not usually cause pain crises unless it's inherited along with the sickle cell gene (HbSC), which can lead to more serious problems like eye disease, bone damage, and spleen issues.

Diagnosis is done using hemoglobin electrophoresis or HPLC, which identifies different types of hemoglobin. A blood smear can show telltale signs like target cells and crystals. Testing is only needed if symptoms are present or if the person has another hemoglobin disorder.

Most people with HbCC do not need treatment, although taking folic acid can help the body make new red blood cells. In people with HbSC, blood transfusions may be used during surgery or pregnancy to reduce complications.

The outlook for people with hemoglobin C disease is generally very good. They usually grow and develop normally and live a typical lifespan. 

Genetic counseling is recommended for couples who may carry the HbC gene. A team approach involving doctors, genetic counselors, and eye specialists may be helpful for those with more complex forms of the condition.

When Is Hemoglobin C Testing Relevant?

Hemoglobin C testing is important for people with inherited blood disorders affecting red blood cells. It’s especially useful in the following situations:

Anemia Symptoms

People with mild hemolytic anemia, where red blood cells break down too early, may be tested to check for hemoglobin variants like HbC.

Family History

If close family members have a hemoglobin disorder, testing can help determine if someone has inherited the same gene.

Ethnic Background

Hemoglobin C is more common in people with West African ancestry, so testing may be recommended based on background.

Newborn Screening

Many states include HbC in newborn blood tests to catch hemoglobin disorders early, even before symptoms appear.

Hemoglobin C Testing: Process and Procedure

The hemoglobin C testing process consists of a few important steps:

Blood Count

A complete blood count (CBC) is done first to check red blood cell levels and size. People with Hemoglobin C disease may have mild anemia, small red blood cells (microcytosis), and target cells (a specific red blood cell shape).

Hemoglobin Analysis

A test called hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) is used to identify different types of hemoglobin in the blood. These tests can detect Hemoglobin C by separating it from other types like HbA and HbS.

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• People with HbAC (trait) usually have about half HbA and half HbC.
• People with HbCC (disease) have mostly HbC.
• People with HbSC disease have both HbS and HbC in nearly equal amounts.

Genetic Testing (if needed)

If results are unclear, DNA testing may be used to confirm the type of hemoglobin variant. Genetic testing is also helpful for family screening or during pregnancy to assess a baby's risk.

Hemoglobin C testing is included in newborn screening in many places, so it can be found early, even before symptoms begin.

What Do Specific Hemoglobin C Test Results Mean?

Specific results may have the following clinical significance:

HbAC (Hemoglobin C Trait)

This means the person carries one gene for Hemoglobin C but usually doesn’t have symptoms or health problems.

HbCC (Hemoglobin C Disease)

This confirms the person has Hemoglobin C disease, which may cause mild anemia due to red blood cell breakdown.

HbSC (Hemoglobin SC Disease)

This result means the person has both Hemoglobin C and S genes. Symptoms vary but may include mild to moderate anemia or other complications.

Other Combinations

Lab tests like hemoglobin electrophoresis or HPLC can detect other hemoglobin variants and mixed types, helping doctors diagnose accurately.

What Does the Absence of Hemoglobin C Mean?

If a test shows no Hemoglobin C, the following clinical scenarios are likely:

Normal Hemoglobin (HbAA)

The person most likely has normal hemoglobin and no HbC-related condition.

Other Hemoglobin Variants Still Possible

Even without HbC, other types of abnormal hemoglobin (like HbS, HbE, or thalassemia traits) could still be present and may require further testing.