Table 2.

Main potential chronic clinical manifestations of SCD in pediatric and adult patients and appropriate diagnostic tools and parameters.

Description	Cause	Features	Diagnostic approach	References
Avascular necrosis	Vaso-occlusion leading to infarction of the articular surfaces and head of long bones	More common in young adults (50% of the patients by 35 years) Involves the hips, shoulders, the knee, the small joints of the hands and spine May be associated with eventual bone collapse Persistent local bone pain and limited motion of affected joints	MRI	(16, 47, 48)
Chronic anemia	Persistent decrease of Hb levels due to repeated hemolysis, with compensation sign	Decreased Hb levels Increased hemolysis indexes Increased reticulocytes Sickle cells	Complete blood investigation including reticulocyte count, LDH and bilirubin, peripheral blood smear	(11, 49)
Chronic pain	Bone infarction, chronic osteomyelitis, leg ulcers, avascular necrosis of the femoral or humeral head	Present on most days over 3–6 months in a single or multiple locations Common in adult patients (40% prevalence) Nociceptive, neuropathic, and central components affecting quality of life Sensation of pins and needles, hyperalgesia, and allodynia and described as numb, tingling, lancinating	Multidimensional assessment (location, type, and pattern of pain), functional limitations patient reported outcomes	(21, 43, 50)
Gallstone disease	Increased hemolysis	Onset in childhood and adolescence, frequent in adults Secondary to chronic hyperbilirubinemia	Abdominal ultrasound	(21, 51)
Leg ulcers	Vaso-occlusion and hypoxia of the skin High hemolytic rate, low Hb May develop without injury or underlying infection	More frequent in adults More frequent in the skin around the ankle, less common in the dorsum of the foot and the anterior tibia	Clinical evaluation, physical examination, laboratory testing	(16)
Ophthalmic disease	Sickling of erythrocytes and increased blood viscosity in HbSC individuals (higher Hb levels) leads to retinal ischemia and scarring Peripheral retinal arteriolar occlusions	Proliferative retinopathy, retinal detachment, vitreous hemorrhage, mainly in young adults but described also in children and adolescents Peripheral retinopathy is more frequent in HbSC and HbS/β+ than in HbSS and HbS/β0 patients	Ophthalmic evaluation	(16, 51)
Pulmonary hypertension	Increased pulmonary pressure (≥25 mmHg), likely due to increased blood viscosity, intravascular hemolysis inducing vascular dysfunction	Mainly in adults Left and right ventricular dilation and diastolic dysfunction Dyspnea, fatigue, increased morbidity and mortality	Right heart catheterization Non-invasive estimation by Doppler echocardiography	(16, 52, 53)
Renal dysfunction	HbS polymerization in the renal medulla	Childhood onset Hyposthenuria, nocturia and enuresis In adolescence frequent renal ischemia, hematuria proteinuria, and hyperfiltration Increased GFR, combined with glomerular hypertrophy results in glomerulosclerosis, and progresses chronic kidney disease and end-stage renal disease in the adult age Increased blood pressure	Evaluation of GFR and proteinuria	(16, 52, 54)

Hb, hemoglobin; HbS, hemoglobin S; HbSC, heterozygous for hemoglobin S and C; HbSS, homozygous for HbS; MRI, magnetic resonance imaging; GFR, glomerular filtration rate.