Sickle Cell Disease: Pathophysiology, Symptoms & Treatment

Introduction to Sickle Cell Disease

Sickle cell disease — formerly called sickle cell anemia — is an inherited disease of the red blood cells. It was first reported in Western medical literature in 1910, when a Midwestern physician described a patient from the West Indies who had an anemia characterized by unusually shaped cells. In the 1920s, it was shown that the transformation of these cells into the characteristic sickle shape was associated with conditions of low oxygen. The abnormal hemoglobin associated with sickle cell disease was first demonstrated in 1948, when the process of protein electrophoresis showed that the hemoglobin in patients with sickle cells was different from that of the average patient.

Before discussing sickle cell disease in depth, it is important to understand the basic pathophysiology surrounding the condition. Hemoglobin is a protein carried by red cells that transports oxygen from the lungs for delivery to peripheral tissues. It is composed of two similar proteins — alpha and beta globin chains — whose coordinated action allows oxygen transport to occur. These two chains combine to form hemoglobin. Throughout life, except during the very first week of embryonic development, one of the globin chains is always an alpha chain. A developing fetus also has a gamma globin chain (sometimes called a non-alpha chain) present in the fetal circulation. The gamma globin is replaced shortly after birth by the beta chain, which then pairs with the alpha chain.

Pathophysiological Basis of Sickle Cell Disease

When two alpha chains combine with two gamma chains, the result is called Hemoglobin F, the predominant hemoglobin of fetal circulation. Adult hemoglobin, formed from two alpha and two beta chains, is called Hemoglobin A. If one alpha and one non-alpha chain combine alone, this two-chain combination is called a dimer and is not functional enough to deliver oxygen to tissues.

Sickle cell disease is most commonly seen in patients of African, Indian, Mediterranean, and Middle Eastern descent. A genetic mutation altered one of the amino acids that build hemoglobin. While the alpha globin remains normal, in sickle cell disease the beta subunit has a substitution of valine for glutamic acid at position six of the amino acid chain. All other amino acids in sickle and normal hemoglobin are identical.

The basis of this mutation is genetic in character. Since DNA determines how amino acids are paired, it is a mutation within the DNA — specifically on chromosome 11, the gene that controls production of the beta subunit — that causes the presence or absence of sickle cell disease. Because of this chromosomal association, sickle cell anemia is an inherited disease.

There are different expressions of this disease. If only one of the beta globin genes carries the "sickle" mutation and the other is normal, that person is considered a carrier. These individuals will not manifest the disease but may pass it on to their offspring; this expression is called sickle cell trait. If both beta globin genes are affected and carry the substitution, the patient has sickle cell disease. Inheritance is the only way of acquiring the condition.

Several factors influence the expression and variability of sickle cell disease. Hemoglobin C on its own generally causes no problems; a person with two genes for hemoglobin C expression may have a relatively harmless condition called Hemoglobin C disease. However, if a patient has both hemoglobin C and hemoglobin S, this is called Hemoglobin SC disease, which can be as severe as sickle cell disease and may also cause red cell dehydration.

As noted, hemoglobin picks up oxygen in the lungs and releases it in the periphery. Normal hemoglobin molecules exist as single units within normal, disc-shaped red cells. Sickle hemoglobin also exists as isolated units within red cells when exposed to sufficient oxygen. In contrast to normal hemoglobin, however, when sickle hemoglobin delivers oxygen to the tissues, the hemoglobin molecules have a tendency to stick together and form long chains.

These chains cause the cell to bend into a crescent, or "sickle," shape — hence the name sickle cell disease. When the cells are re-oxygenated, they resume their normal shape. This repeated shape-shifting causes physical damage to both the red cell and the hemoglobin. Ultimately, the sickled hemoglobin reaches a point where it can no longer revert to single strands; instead, it becomes twisted into long, braided bundles. These bundles associate into even larger structures that stretch and distort the cell. As one description puts it: "The analogy would be a water balloon that was stretched and deformed by icicles. The stretching of the balloon's rubber is similar to what happens to the membrane of the red cell. Polymers tend to grow from a single start site, called a nucleation site, and often grow in multiple directions. Star-shaped clusters of Hemoglobin S develop commonly."

The Hemoglobin S that appears in the sickling situation is maintained as a polymer group only by the weakest of forces. The association of valine with the beta chain makes the bonds between the twisted hemoglobin structures very weak. Unfortunately, the polymerization that occurs in sickling cells not only changes cell shape but also makes cell walls rigid. The cells may become wedged in smaller blood vessels, causing micro-infarction to local tissue. The end result is pain and often organ damage due to hypoxia. This cellular damage also underlies many of the complications of sickle cell disease. Free heme can be released from cells during repeated cycles of polymerization and depolymerization, resulting in the formation of reactive oxygen compounds. Antibodies can develop against these compounds, attacking the red cells themselves and causing even greater hemolysis and a higher degree of anemia than is already produced by red cell destruction alone.

The bone marrow attempts to compensate by increasing red cell production, but in most patients it cannot keep pace. As a result, the volume of active bone marrow in sickle cell patients is much greater than in individuals with normal hemoglobin.

Physical Manifestations of Sickle Cell Disease

The severity of anemia varies from patient to patient. A typical patient with sickle cell disease will have a hematocrit of around 25%, compared with approximately 45% in a normal individual. The pattern of disease expression also affects the degree of anemia. For example, patients with Hemoglobin SC disease (one beta globin coded for S and one coded for C) have higher hematocrits than patients with Hemoglobin SS disease (both beta globins coded for S). Patients with sickle cell trait have normal blood counts.

People with a family history of sickle cell disease are understandably concerned that they may carry or have the disease, and often seek testing. Routine complete blood counts (CBCs) cannot identify sickle cell disease. The best diagnostic test is hemoglobin electrophoresis, which can detect the different hemoglobins and can also identify whether the patient has Hemoglobin C or thalassemia. Most newborns in the United States are screened at birth for these conditions.

The most common presentation of sickle cell disease in adults is what is called a vasoocclusive crisis. This typically begins in response to some change in the body — such as fever, high altitude, or even temperature changes on a hot day — though sometimes no triggering cause can be identified.

The most common symptom is severe, deep pain in the extremities, usually involving the long bones. The abdomen is another frequent site of pain. The pain is usually very severe and may be accompanied by fever, malaise, and leukocytosis. This syndrome may last anywhere from a few hours to several days, often beginning and ending abruptly. Anemia is universally present and may serve as a diagnostic clue in a previously undiagnosed patient. As noted above, the anemia is chronic and hemolytic. Megaloblastic changes may be seen due to rapid cellular turnover and folate deficiency. In the worst cases, an aplastic crisis may occur, often associated with Parvovirus B-19 infection, in which the bone marrow's replacement of red cells is disrupted and hemoglobin levels fall rapidly. Fortunately, this condition is usually self-limited and primarily managed with supportive care. Recovery is typically heralded by a rise in the reticulocyte count.

In children and adolescents, sickle cell disease causes growth retardation, delayed development of secondary sexual characteristics and sexual maturation, and significant underweight. During childhood, the spleen often enlarges — especially during the first year of life — due to sequestration of large numbers of sickled cells. This is a painful process. The spleen then undergoes repeated infarcts, and splenic function becomes impaired during the period of enlargement. Eventually, repeated infarction leaves the spleen fibrotic and shrunken, rendering it non-functional — a process referred to as autosplenectomy. The absence of functional splenic tissue leaves sickle cell patients immunodeficient and particularly vulnerable to encapsulated organisms such as Streptococcus pneumoniae. Pneumococcal infections are common in childhood, while infections with gram-negative organisms are common in adult life.

Infants with sickle cell disease often suffer from dactylitis, which causes painful swelling on the dorsum of the hands and feet and can result in cortical thinning of the bones. A syndrome called acute chest syndrome is also seen, characterized by chest pain, fever, rapid breathing, and pulmonary infiltrates on chest X-ray. Acute chest syndrome is considered a medical emergency, as it may rapidly progress to acute respiratory distress syndrome and death if not treated promptly.

The central nervous system is not spared from the effects of sickle cell disease. The most prevalent neurological manifestation is embolic stroke, which may produce varying degrees of neurological deficit. The cardiovascular system may also be affected, since chronic recurrent hemolysis can lead to hemosiderin deposition within the myocardium, causing ventricular dilation and congestive heart failure. Additional complications include gallbladder disease, repeated infarction of the joints and bones, pulmonary hypertension from repeated micro-infarction, and renal failure secondary to loss of concentrating ability.

Patients may also lose vision due to retinal vascular infarcts. Leg ulcers are a common and painful complication; because of the poor circulation associated with the disease, healing is impaired and infection is frequent.

Conclusion

Patients who suffer from sickle cell disease have a chronic, disabling, and potentially life-threatening disease that manifests almost from the time of birth. This disease may be one of the most studied and possibly one of the most well-understood conditions on a pathophysiological basis, yet no cure exists. Patients require comprehensive care and careful attention to the prevention of crises.