For a young African-American patient presenting with a history of joint pain, bone pain, abdominal pain, and anemia, the most likely diagnosis is SCD. Other diagnoses to consider include other hemoglobinopathies, dermatomyositis, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and porphyria. Nevertheless, given the constellation of symptoms and the laboratory findings, SCD is the most likely diagnosis. A hemoglobin (Hgb) electrophoresis will confirm the diagnosis and provide the percentage of abnormal hemoglobin S (HgbS).

SCD is a hereditary hemoglobinopathy resulting from inheritance of a β–globin gene mutation located on chromosome 11. This mutation leads to a single-point mutation where adenine is replaced with thymine. The mutant β-allele codes for production and assembly of a variant Hgb (β-S). The molecular basis of SCD has been demonstrated to be the substitution of valine for glutamic acid in the sixth position from the N-terminus of the β-chains of Hgb. This substitution replaces a hydrophilic negative-charged amino acid (glutamic acid) with a hydrophobic nonpolar amino acid (valine). This greatly destabilizes the structure of Hgb and exposes highly reactive hydroxyl groups on the protein surface. The mutation in β-S Hgb accelerates the denaturation of the Hgb molecule and significantly decreases its solubility. Decreased oxygen tension causes conformational changes in the Hgb molecule, allowing hydrophobic bonds to form between the BS-6 valine of one chain and the BS-85 phenylalanine and the BS-88 leucine of a second chain. This bond forms insoluble tetramers that bond with other tetramers to form long helical strands that subsequently polymerize, causing deformation of the red blood cell membrane into a sickle shape. The result is a red blood cell that is less able to transverse the capillaries of the microcirculation, disposing the end organ to hypoxia and ischemic damage when sickle cells are present in sufficient quantity. In the United States, the estimated prevalence of Hgb SS disease is 1:625 (0.2%) in people of African descent. Patients with SCA have early mortality, with the median age of death in the late 40s to early 50s.

SCT is the heterozygous or carrier state of SCD. Large-scale screening for SCD in American military recruits revealed an incidence of SCT (HbAS) of 8% to 10% in African Americans and 0.05% to 0.08% in others. HbAS cells begin to sickle only when oxygen saturation of Hgb is less than 20%. No difference has been found between normal persons (HbAA) and those with HbAS regarding survival rates or incidence of severe disease, with one exception: Patients with HbAS have a 50% increased risk for pulmonary infarctions. Studies have suggested that SCT provides a survival advantage over hematologic normal individuals when infected by the malarial parasite Plasmodium falciparum.

The most common hemoglobinopathies include the thalassemias, Hgb C disease, and SCA. Thalassemia arises from alterations in one or more of the four genes that code for the α-chain. The mildest form of thalassemia (loss of one α-gene) presents as a mild form of anemia, whereas the most severe form (loss of all four genes) is incompatible with life. Hgb C results from a mutation in the β–globin gene. Hgb C disease is a relatively benign disease producing a mild hemolytic anemia and splenomegaly. However, when it is paired with a β-S mutation, the disease is more severe. Other rare hemoglobinopathies will not be discussed further.

Each Hgb gene mutation of the heterozygous form causes little or no clinical consequence, but when both genes of a heterozygote are abnormal, a disease state is evident. Heterozygous combinations such as HbS and HbC (HbSC disease), and β-thalassemia mutation (HbS-β-thalassemia) usually cause a milder clinical course than that of SCD.

The clinical features of SCD are manifested through indolent end-organ damage with intermittent acute episodes of severe pain and pulmonary complications. Although SCD is a disease of Hgb, it ultimately affects all organ systems. It is usually the acute problems that bring these individuals to the attention of a physician. The clinical manifestations by organ systems are presented in Table 32.1.

The progression and severity of SCD is variable. Many of the patients have an indolent course, whereas a smaller subset suffer from an early end-organ failure and an early death. Pulmonary, neurologic, and renal disease are the leading causes of morbidity and mortality.

Sickle cell crisis refers to the acute clinical picture generally caused by sickling of red blood cells in the microcirculation. Four main clinical types of crises have been described as follows in Table 32.2.

The most common crises in SCD is vaso-occlusive crisis, which is characterized with intermittent, recurrent acute episodes of severe pain. It is generally felt that the central cause of pain is ongoing acute ischemia, vaso-occlusion, and infarction. The precise pathophysiology and nociceptive pathways have not been elucidated. Patients in vaso-occlusive crisis present with fever, anemia, spine pain, limb pain, and abdominal pain. They are tachypneic and may have an enlarged liver and spleen in addition to abdominal tenderness. Serjent et al. reported that in 118 patients having 183 painful crises, the location was noted to be in the lumbar spine (49%), abdomen (32%), femoral shaft (30%), and the knee (21%). There is usually no identifying triggering agent for most vaso-occlusive crises. The average rate of painful crises per patient year is 0.8%. There is a subset of patients (5.2%) who average 8 to 10 crises a year, which accounts for 33% of all hospitalizations. Mortality positively correlates with increased pain rate in adults.