Sickle Cell Disease and Its Impact on the Body

Sickle cell disease (SCD) is the most common hemoglobinopathy among people in the United States. Hemoglobinopathy is a group of inherited disorders in which there is abnormal production or structure of the hemoglobin molecule. Sickle cell disease is an autosomal recessive disorder and a global health problem.

SCD occurs when there's a singular amino acid alteration in one protein, causing it to polymerize (form fibers and make the cells less flexible) and create what looks like a rod, explained Stuart Orkin, M.D., the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School and a Howard Hughes Medical Institute investigator.

"That rod basically damages red blood cells, and a damaged red blood cell has a shortened half-life," said Orkin, who is also affiliated with the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. He received the 2022 Canada Gairdner Award for discovering the molecular mechanism that causes the switch from fetal to adult hemoglobin gene expression, and for applying that discovery to the innovative treatment of a disorder such as sickle cell disease.

Sickling disorders are inherited diseases that affect hemoglobin within red blood cells, according to Cage Johnson, M.D., a professor emeritus of medicine in the division of hematology at the University of Southern California Keck School of Medicine in Los Angeles and a past director of the Sickle Cell Center there.

"This group of diseases is found in high frequency in sub-Saharan Africa, the Mediterranean countries, the Middle East and India, but is also widely distributed throughout Europe and the United States, as well as Central and South America," he said.

An estimated 100,000 people in the U.S. have sickle cell disease, according to the Centers for Disease Control and Prevention (CDC). Approximately 1 in 13 Black children in the U.S. are born with the trait for the disease, and SCD occurs in about 1 in 365 Black births.

Sickled cells—those shaped like a crescent moon, resembling the sickle traditionally used for harvesting—are produced by polymerization and cause obstruction of blood vessels, which leads to reduced blood flow (ischemia), tissue death (infarction), anemia and morbid complications, Johnson explained.

Orkin said the damage to small vessels in patients with SCD is caused by the rod-shaped cells becoming rigid and getting stuck, which can cause terrible pain, tissue damage and strokes.

Sickle cell anemia is often the most severe form of SCD, occurring in people who have inherited a sickle cell gene from each parent. Symptoms associated with sickle cell anemia usually start by age 5, Johnson noted. Symptom onset with the other SCD genotypes is variable up to early adulthood.

"The diagnosis is made by electrophoresis of hemoglobin into its component parts and quantification of these components," Johnson explained.

Where quality medical care is available, Orkin said screening for newborns that requires only a small amount of blood is standard.

According to a study published in 2013, SCD had a mortality rate of 0.2 per 100,000 people in the U.S., regardless of race, between 1999 and 2009.

The authors wrote: "When compared to 1979-1998, there were nonsignificant declines in sickle cell-related mortality in early adulthood up to age 34; with decreases of 7 percent for individuals age 20-24 years and 2 percent for those age 25-34 years. However, during both study periods, black individuals 35-44 years of age had the highest mortality rate at 2.1 per 100,000 population."

In comparing SCD-related deaths between 1979 and 1998 with those that occurred between 1999 and 2009, the authors confirmed a decrease in childhood mortality, but they also reported that "individuals with SCD live on the average 30 years less than the general population."

That situation hasn't changed much, and many SCD patients die between their mid-30s and mid-50s.

"It's a dreadful disease because the damage keeps on accumulating over time," Orkin said. "Children will have painful episodes; they might even have strokes. But the adults have this accumulated damage, and it's just debilitating in terms of organ damage, pain."

He said patients often require pain medications and may become addicted, which can lead physicians to question the motives of SCD patients when they seek the drugs, despite the prolonged agony the disease regularly entails. Orkin called it a vicious circle.

SCD makes it incredibly difficult for afflicted adults to lead normal lives, Orkin said.

For example, Ernie McGee, a longtime resident of Moreno Valley, California, has a daughter with sickle cell disease. He said doctors misdiagnosed his daughter, Marlo McGee, 45, a number of times when she was a child. They said nothing was wrong with her. She was finally diagnosed correctly as a teenager, but despite recurring pain and being at greater risk for SCD because she's Black, she was never referred to a specialist, her father said.

During an emergency room visit several years ago, a physician believed McGee was faking and merely seeking sympathy. Only later did the doctor realize the disease had destroyed her spleen. McGee also had to undergo hip surgery because of her sickle cell disease.

"It does damage to circulation," the elder McGee said, adding that he has witnessed the disease wreak havoc on Marlo since childhood.

He finally realized, some 27 years after his daughter first showed symptoms, that people with SCD are "never fine."

Editor's note: Next week, we'll follow up on Marlo McGee's case and take a look at how sickle cell disease is treated, including how still-in-its-infancy gene therapy may play a role in the near future.