What is Hemoglobin C Disease?
Hemoglobin is a vital protein present in our red blood cells that is made up of four chains of globin protein: a pair of ‘alpha’ chains and a pair of ‘non-alpha’ chains. These chains shape the hemoglobin structure by forming grooves on the protein’s surface where the heme groups sit. The heme groups are what allow hemoglobin to carry oxygen from our lungs to the rest of our bodies.
Testing hemoglobin can reveal three normal types in adults. These include Hb A (making up 95 to 98% of our hemoglobin), consisting of two alpha and two beta chains; Hb A2 (2% to 3%) which has two alpha and two delta chains and; Hb F (less than 1%) with two alpha and two gamma chains.
However, there is also a variant called Hemoglobin C (Hb C), where a portion of the regular hemoglobin is replaced with lysine, resulting in a protein less soluble than Hb A. Hb C can exist in two forms – Hb CC, where the individual inherits the variant from both parents, and Hb SC or Hb AC, where the variant is inherited from one parent. People with the Hb AC trait don’t usually show symptoms, but those with Hb CC might experience mild, chronic breakdown of red blood cells, an enlarged spleen, and jaundice (a yellowing of the skin and eyes from excess breakdown of red blood cells).
Although Hemoglobin C disease is mild and doesn’t typically cause severe problems, when it’s combined with other genetic blood disorders like hemoglobin S, it can lead to serious health issues. Therefore, these patients should receive careful medical attention, treatments and genetic counseling to understand the implications of their conditions.
What Causes Hemoglobin C Disease?
Hemoglobin C is a condition that happens when there’s a change in the beta-globin chain part of our blood. Here, a substance called glutamate is replaced by another called lysine. This change makes Hemoglobin C less soluble, or unable to dissolve as well, compared to normal hemoglobin (Hb A). As a result, it forms a certain kind of crystal structure.
Hemoglobin C is a hereditary condition, meaning it can be passed down from parents to their children. It’s what we call an autosomal recessive disorder, meaning both parents must carry the gene that causes Hemoglobin C for a child to have the disease. If both parents are carriers, there is a 25% chance of having a child with Hemoglobin C disease, a 50% chance of having a child who is a carrier but doesn’t have the disease, and a 25% chance of having a child who neither carries the gene nor has the disease.
Interestingly, some forms of this illness, including Hemoglobin C, might have developed evolutionarily as a defense against malaria. In the carrier form, these changes in the gene can help protect against death from malaria. Research with children in Mali found that carriers of Hemoglobin C had protection against a type of malaria. Additional studies suggest that these changes in the hemoglobin might disturb the malaria parasite’s ability to affect red blood cells – a process involved in the disease.
A separate study focusing on patients with sickle cell disease who had a red blood cell exchange transfusion found the presence of Hemoglobin C in the patients, which was acquired as a result of the treatment.
Risk Factors and Frequency for Hemoglobin C Disease
Hemoglobin C, which helps protect against malaria, is quite prevalent in Atlantic West Africa and Southeast Asia due to its beneficial effects. It can also be found in various populations in Africa, South and Central America, and Southern Europe.
A study that looked back at 111 cases of hemoglobin C disease over a period of 12 years in Morocco, found that the average age when people were diagnosed was 38 years old, but it ranged from 4 to 80 years old.
- Of the people in the study, 75% had a type of the disease known as heterozygous A/C.
- 8% were the homozygous C/C type.
- 9% had the double heterozygous S/C type.
- 6% had C/beta +/- Thal.
- And, 2% had C/O – Arab.
Signs and Symptoms of Hemoglobin C Disease
The Hemoglobin C trait and Hemoglobin C disease are usually mild and do not cause any noticeable symptoms in most people. However, some people with Hemoglobin C disease may experience mild symptoms related to anemia, such as feeling tired, light-headedness, weakness, and pale skin. During a physical examination, doctors may find mild to moderate spleen enlargement and, less commonly, jaundice (yellowish skin). Notably, a past study involving 111 people with Hemoglobin C disease found the main reasons people were tested for this condition were an enlarged spleen and anemia. Some individuals, due to continued breakdown of red blood cells, may develop gallstones, which are often dark colored.
People with a combination of sickle cell and Hemoglobin C disease tend to have symptoms similar to, but less severe than those with Hemoglobin SS disease. As Hemoglobin C does not form long chains like Hemoglobin S, red blood cells do not take a sickle shape as frequently, reducing the chances of a sudden blockage of a blood vessel. A study comparing sickle cell anemia and Hemoglobin SC disease found that Hemoglobin SC was more associated with increased thickness of the blood, while Hemoglobin SS was more often associated with abnormally shaped red blood cells and blood vessel damage. Notably, negative health events were more common in people with Hemoglobin SS.
Two complications that seem to occur more often in people with Hemoglobin SC disease are an eye condition called vascular retinopathy and hip bone damage called avascular necrosis of the femoral head. In a study of 461 infants with Hemoglobin SC disease, there were a few notable observations:
- Almost 15% had acute splenic sequestration (sudden, severe spleen enalargement)
- 0.2% had an apparent stroke
- The rate of painful episodes due to blocked blood vessels was 51 per 100 patient-years
- The rate of infections was about 62 episodes per 100 patient-years
- Of the 59 children who had eye tests, retinopathy was observed in over 20%
- Of 12 patients examined, seven had avascular necrosis, mostly in the left femur
Testing for Hemoglobin C Disease
If you don’t show any symptoms, routine blood tests aren’t required. Yet, if your symptoms are moderate to severe, a doctor may order tests to evaluate your condition. The results of these tests can vary depending on whether you carry the trait for Hemoglobin C (HbAC) or have Hemoglobin C disease (HbCC).
Hemoglobin C, in both cases, causes your red blood cells to lose water and become dehydrated. This leads to higher than normal levels of hemoglobin within each red blood cell, which is also known as an increased mean corpuscular hemoglobin concentration (MCHC).
The most common way to identify hemoglobin-related disorders is through methods like hemoglobin electrophoresis or high-performance liquid chromatography (HPLC). If you have Hemoglobin C disease, the results mostly show a high amount of Hemoglobin C (HbC), no normal adult hemoglobin (HbA), and slightly increased levels of fetal hemoglobin (HbF). Those who are carriers for Hemoglobin C disease may show 30% to 40% Hemoglobin C, 50% to 60% regular adult hemoglobin, and slightly increased levels of Hemoglobin A2.
A blood smear test can reveal the presence of unique crystal shapes in your blood cells due to less soluble Hemoglobin C. It can also show small-sized red blood cells (microcytosis), irregular cells, and numerous target cells.
Those who carry only the trait for Hemoglobin C usually have normal to slightly low hemoglobin levels. While the lifespan of their red blood cells is reduced, their body doesn’t produce a higher number of new red blood cells (reticulocytes). Likewise, people with Hemoglobin C disease can show signs of hemolysis (destruction of red blood cells), which may lead to increased levels of LDH, reticulocytes, and direct bilirubin. They may also exhibit microcytosis, target cells, spherocytes, and crystal-like structures in their red blood cells.
An interesting fact is that patients with Hemoglobin C or S who also have diabetes can show falsely low levels of glycosylated hemoglobin (HbA1c), a blood sugar marker, despite having consistently high blood sugar levels. This discrepancy is related to the presence of abnormal hemoglobin.
Recently, advances have been made in developing tests for hemoglobin-related disorders that are practical and affordable, especially for low-resource settings. For instance, paper-based microchip electrophoresis has shown a high sensitivity and accuracy in identifying hemoglobin variants. Additionally, automated techniques and new polymerase chain reaction tests can provide large-scale confirmatory testing for hemoglobin mutations, which are particularly useful for diagnosing conditions like sickle cell disease.
Treatment Options for Hemoglobin C Disease
For most people, no particular treatment is needed. However, similar to chronic cases of excessive red blood cell breakdown, the body’s stores of a vitamin called folic acid might get used up. Taking folic acid supplements can help because this vitamin assists in producing new red blood cells and can alleviate the symptoms of anemia, which is a condition where your blood does not carry enough oxygen to the rest of your body because of a lack of healthy red blood cells.
Despite having an enlarged spleen, or splenomegaly, the spleen continues to work normally. So, long-term use of preventive antibiotics is usually not required.
A study found that in patients with a type of sickle cell disease called hemoglobin C disease who were undergoing a type of surgery known as cardiopulmonary bypass, using a procedure called complete exchange blood transfusion made the surgery relatively safer and improved its outcomes. Exchange blood transfusion is a procedure that replaces your sickle cells with normal red blood cells.
Similarly, another study showed positive results for both mother and baby in pregnant individuals with hemoglobin C disease who received preventive blood transfusions. These are just given as precautions to prevent complications.
What else can Hemoglobin C Disease be?
When doctors suspect a patient might have Hemoglobin C disease, there are other conditions they need to rule out because they present similar symptoms. These include:
- Sickle cell anemia
- Beta thalassemia
- Other types of hemolytic anemias
What to expect with Hemoglobin C Disease
Hemoglobin C is a non-harmful condition that can lead to a mild type of anemia known as “hemolytic anemia.” Hemolytic anemia is a disorder where red blood cells are destroyed faster than they can be produced. Despite this, individuals with Hemoglobin C generally grow and develop normally and are expected to live a full lifespan.
Possible Complications When Diagnosed with Hemoglobin C Disease
Hemoglobin C disease can cause the prolonged breakdown of red blood cells, leading to cholelithiasis, a condition where pigmented gallstones form in the gallbladder.
Furthermore, those with a combination of sickle cell disease and hemoglobin C disease (referred to as HbSC) may experience various complications. These can include:
- Vascular retinopathy, which is damage to the small blood vessels in the eye,
- Avascular necrosis, a condition that arises when there is a loss of blood to the bone, often resulting in tiny breaks and eventual bone collapse,
- Renal medullary microvascular thrombosis, a condition characterized by clot formation in the small blood vessels within the innermost part of the kidney (the renal medulla).
Studies performed on individuals with hemoglobin SC disease have also indicated potential abnormalities in the capillary basement membrane, predominantly located in the renal medulla. These abnormalities are often accompanied by thrombi, or blood clots, in the peritubular capillary and vasa recta, showing the disease’s impact on the kidney’s blood vessels.
Preventing Hemoglobin C Disease
Hemoglobin C disease is a mild condition and typically does not require any treatment. Patients aren’t required to limit their physical activity nor follow any specific diet. However, for couples who carry a high risk of passing on Hemoglobin C disease and want to have a child, it could be useful to speak with a genetic counselor. These professionals can provide advice and guidance on the matter.
