History lets us know that sickle cell trait (SCT) has been present as far back as approximately 7,000 years ago, possibly even before then. With the contributions of epidemiologists and researchers, we learned that sickle cell trait developed as a protective measure against the effects of malaria. For an individual with SCT, when a malaria parasite infects a red blood cell, the red blood cell can sickle because of low oxygen. Red blood cells that sickle are destroyed along with the malaria parasite. Fascinating, right? Individuals with SCT can still be infected with malaria although the severity of the symptoms may be decreased due to this proposed theory. While sickle cell trait can provide that advantage, we soon learned what could happen if two parents with SCT passed down their genes to their children—it could lead to sickle cell disease. From there, research shifted and explored more of the effects of sickle cell disease on the body. Yet, it’s so important to take a step back to understand sickle cell trait in its totality. Let’s take a journey inside to learn more about sickle cell trait.
To understand sickle cell trait, we have to understand the beauty that is genetics. We can think of all the genes that we have—our genome—as the foundational “book” that has the instructions of how we are made. We have many genes, just as a book has many sentences. Each gene includes information on our eye color, how long our legs will be, how many hairs on our head we will have, and especially whether we will have sickled red blood cells or normal red blood cells. With sickle cell trait, there is a specific gene that tells our bodies how to make our hemoglobin for our red blood cells. Hemoglobin is a protein that helps our red blood cells carry oxygen throughout our bodies – like from our lungs when we inhale it to our liver, where it will then use that oxygen to create energy for the liver cell to detoxify substances. In sickle cell trait, the hemoglobin gene or “sentence” will have one “letter” that is changed; that change is called a genetic mutation. In this case, the genetic mutation now tells our body that it will make red blood cells that will turn into a crescent or sickle shape under certain conditions, like when oxygen decreases or if our body becomes acidic.
Our red blood cells appear sickled because hemoglobin HbS changes shape. There are many hemoglobin proteins inside each red blood cell. Usually, they like to “roam around” the red blood cell having their own space to do so. However, when each sickle hemoglobin (HbS) drops off oxygen to a cell or a tissue, the hemoglobin will change its shape, making other nearby hemoglobin S start to stick together so that they create long lines within the red blood cell. This is what causes red blood cells to become crescent shaped.
We receive two copies of a gene—one from each parent, and we call this our genotype. In sickle cell trait, one copy of hemoglobin has the instructions for a normal hemoglobin (HbA) and the second copy has the instructions for a sickled hemoglobin (HbS). So, the body will create both hemoglobin types, where in sickle cell trait, HbS is in much smaller amounts (anywhere between 25% to 50%) than the amount seen in sickle cell disease. Each type, HbA and HbS, will live in each red blood cell.
If HbA and HbS are in each red blood cell, how come red blood cells are still mostly round? Genetically, HbA is a dominant gene, meaning it is expressed stronger than the recessive gene, which is HbS in this case. Also, with sickle cell trait there are much more HbA present in each red blood cell than there are HbS, meaning more of the hemoglobin stay in their space and don’t form long lines. Thus, each red blood cell will look like a normal red blood cell. How we see genes expressed physically is called the phenotype.
As mentioned earlier, the amount of hemoglobin HbS in sickle cell trait is much smaller compared to the amount seen in those with sickle cell disease, and so, it’s not enough to cause sickling as easily as in sickle cell disease. It’s when there are extreme conditions happening within the body (or a result of activity outside of the body) that sickling can occur. One example of an extreme condition is low oxygen levels in the body. In sickle cell disease, sickling occurs regardless of oxygen levels; it is the high amount of HbS present in each red blood cell (~80%) that dictates how much sickling occurs. In sickle cell trait, sickling only occurs because of low oxygen or another extreme condition within the body.
Because HbA is dominantly expressed, and each red blood cell is normal in shape, individuals with sickle cell trait generally do not experience major health problems as a result of the sickle gene. Sickle cell trait generally does not cause vaso-occlusive crises. Those with sickle trait also generally do not have an increased risk of mortality compared to the general population. They can even donate blood, organs, or tissues.
The kidneys can be an organ of concern for those with sickle cell trait. The renal medullae within the kidneys can have low levels of oxygen for various reasons, which causes sickling. This sickling in the kidneys can lead to major kidney health problems, which will be discussed in detail below.
Under certain circumstances, other genetic changes, or other health conditions, individuals with sickle cell trait may experience complications, which will also be discussed below.
There are some complications that a person with sickle cell trait can experience. Each person with sickle cell trait has a different experience from another person. Many may never experience any of these, while some may. Nonetheless, knowing these helps to stay informed.
Exertional stress, rhabdomyolysis, and metabolic acidosis
In sickle cell trait, exertional stress, like physical training beyond the limits that a person can tolerate, often leads to sickling and can create a number of harmful effects. Sickling in sickle cell trait can be the same as seen in sickle cell disease—sickling can block blood vessels in lungs, the heart, the brain, muscles, and other tissues and organs. Exertional stress can result from extreme physical exertion/intense exercise, activity duration and recovery, dehydration, and climate effects (usually heat but can also occur during very cold temperatures).
During intense activity, muscle tissue can break down, which is called rhabdomyolysis, and can release a protein called myoglobin and other cell substances into the blood. Eventually, these make their way to the kidneys and can harm the kidneys.
Most substances inside cells are harmful when dumped into the bloodstream, which is why our bodies create strong cell membranes to prevent this from happening. So, when red blood cells break down or muscle tissues break down and release their contents, it can make the bloodstream acidic. In addition, during extreme physical exertion, electrolyte levels can become unbalanced. When all of these occur, this is called metabolic acidosis and can lead to organ damage or failure.
Exercise-related sudden death
If sickling, tissue damage, muscle breakdown, and organ damage continue as a person with sickle cell trait keeps exerting themselves and not stopping, eventually this may lead to exercise-related sudden death. Even though those, particularly athletes, with sickle cell trait potentially are at a greater risk for sudden death compared to those without sickle cell trait, it is still rare and does not occur as often as may be portrayed. Proper exercise protocols, warm up activities, and proper hydration can help decrease such risk. Nonetheless, because it can occur, it is still important to note so that those with sickle cell trait take the necessary precautions.
Splenic infarction can occur in sickle cell trait when sickling occurs, although it is a rare complication. Research has found that splenic infarction in sickle cell trait is most likely due to dehydration in athletes and in those with sickle cell trait who are at high altitudes of about 5,000 to 7,500 feet above sea level. To give context, sea levels of some major cities are listed below.
Chronic Kidney Disease (CKD)
Older adults with sickle cell trait have an increased risk for chronic kidney disease, particularly in African American and Caribbean populations due in part to comorbidities, like hypertension and Type II Diabetes. CKD affects approximately 15% to 35% of adults over the age of 45 years. In the kidneys, the renal medulla can have low levels of oxygen for a variety of reasons that are specific to each person. Reduced oxygen levels in the renal medulla can lead to sickling and can damage parts of the kidneys.
Interestingly, some reports have shown that, if a person with sickle cell trait also inherits the gene for α-thalassemia, they will make less hemoglobin type S, so they will experience less sickling in the kidneys. So, α-thalassemia can offer protective effects in sickle cell trait just as in sickle cell disease.
Renal Medullary Carcinoma (RMC)
Renal medullary carcinoma is an extremely rare, yet aggressive cancer. It tends to be diagnosed when it has already metastasized or moved to other regions of the body. Once RMC reaches metastasis, mortality risks are significantly higher, so it’s important that those with sickle cell trait collaborate with their doctors to ensure proper kidney health and the absence of this cancer, even if it is rare.
While researchers are still trying to understand the full cause(s) of RMC, they are finding that the continuous sickling in the renal medulla plays a role. Other things may contribute as well like whether certain genes that prevent cancer are turned “on” or “off”.
RMC tends to occur most often in children and young adults less than 21 years of age. Early signs of hematuria (blood in urine) and pain on one side of the body between the abdomen and back may indicate that a doctor should conduct a full workup to evaluate for a potential kidney complication, like RMC. Hematuria alone, which is common in adults with sickle cell trait, may not always mean RMC is present; however, if a child or young adult who is known to have sickle cell trait suddenly starts showing signs of hematuria, let their physician know to immediately begin testing for overall kidney health.
We encourage those with sickle cell trait to take care of their health by staying hydrated and eating a balanced, nutritious diet. It is also important for individuals with SCT to listen to their bodies especially during physical activities or when in regions with low oxygen levels, like high altitudes/mountain climbing or deep sea/scuba diving. Individuals with sickle cell trait should encourage any other family members to get screened if they haven’t already done so to know their genotype and make informed decisions about their health. It is also important to attend healthcare appointments and annual physicals regularly, and ensure that the healthcare provider conducts all appropriate labs and reviews the health of all organs, especially the kidneys.
Having sickle cell trait does not have to create fear or negative perceptions because many individuals with sickle cell trait lead normal, healthy lives with no complications. Staying informed and knowing that health is wealth means you’re on the right path!