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Disease-a-Month ] (2017) ]]]–]]]

Contents lists available at ScienceDirect

Disease-a-Month

journal homepage: www.elsevier.com/locate/disamonth

Sickle cell disease; An overview of the disease


and its systemic effects
Sahar Alrayyes a,g, Danny Baghdan b,
Rami Y Haddad, MD, FACPi, Anne-Ashley Compton a,c,
Sandra Mohama d, Reihaneh Goreishi e, Nadia Kawar f,h,*
a
Diplomate, American Board of Pediatric Dentistry, USA
b
Loyola University School of Public Health, IL, USA
c
Private Practice, IL, USA
d
Dominican University, IL, USA
e
Postgraduate Periodontics Program, College of Dentistry, University of Illinois, USA
f
Diplomate, American Board of Periodontology, USA
g
Clinical Associate Professor, Department of Pediatric Dentistry, College of Dentistry,
University of Illinois, USA
h
Clinical Associate Professor, Department of Periodontology, College of Dentistry, University of Illinois,
USA
i
Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois

Introduction

Sickle cell disease (SCD) is an inherited red blood cell (RBC) disorder caused by the presence of an
abnormal hemoglobin, called hemoglobin S (HbS) or sickle hemoglobin. It is the most prevalent
genetic blood disorder worldwide.1,2 The two major characteristics are chronic hemolytic anemia
and intermittent vaso-occlusion that results in tissue ischemia causing acute, severe pain episodes.
SCD is a chronic disease that has detrimental effects on the entire body and requires a
multidisciplinary team for management. The purpose of this paper is to provide a broad overview
of the numerous systemic effects that SCD has on patients.

Pathophysiology

Hemoglobin (Hb) is the oxygen carrying protein in the blood with normal Hb consisting of a
heterotetramer composed of 4 proteins, 2- α globins and 2-β globins. Abnormal sickled hemoglobin
(HbS) occurs as a result of a single amino acid substitution on the β-globin gene (HBB).3 This nucleotide

*
Corresponding author at: Department of Periodontology, College of Dentistry, University of Illinois, USA.
E-mail address: kawarnad@uic.edu (N. Kawar).

https://doi.org/10.1016/j.disamonth.2017.12.003
0011-5029/& 2017 Elsevier Inc. All rights reserved.
2 S. Alrayyes et al. / Disease-a-Month ] (2017) ]]]–]]]

substitution occurs on the 6th codon of the HBB gene when the normal hydrophilic glutamic acid is
replaced with a hydrophobic valine residue, resulting in polymerization of an abnormal, less soluble HbS
upon deoxygenation.3,4 Sickle cell disorders are classified by the number of globin genes that are
affected and inherited in an autosomal recessive manner. The heterozygous form is when the individual
only carries one gene for HbS and is called sickle cell trait. It occurs frequently in individuals of African
ancestry with 8% to 10% of African Americans carrying the trait.5 This form is the relatively milder form
of SCD; the affected individual will not show any symptoms and no treatment or precautions are
needed. The homozygous state, called sickle cell anemia (HbSS), is the most common and severe form of
SCD and accounts for 60–70% of SCD in the United States (US).3 In HbSS, the RBCs become distorted and
sickle shaped when blood experiences deoxygenation, decreased pH-; if the patient has a fever,
becomes dehydrated or stressed. The distortion of the RBCs causes partial crystallization of HbS and
polymerization, which forms rigid polymers that repeatedly form and damage the RBC membrane,
shortening the RBC lifespan.5 The average lifespan of RBCs in HbSS is 12–17 days (compared to the
normal 120 days).4,6 Additionally, RBCs become dehydrated, exhibit cellular rigidity and become
abnormally adhesive, causing it to stick to the endothelium of blood vessels, impeding blood flow. This
obstruction of the microvascular is called vaso-occlusion, and leads to ischemia, infarction and ischemia-
reperfusion injury to multiple organs and tissues, which produces a chronic inflammatory response and
vascular dysfunction that can cause severe pain and eventually organ failure.4,7

Prevalence

The World Health Organization (WHO) and the United Nations (UN) declared SCD a public health
burden, as there are over 300,000 affected births each year.8–10 The global epidemiology of HbS
reveals a high frequency of patients with SCD across most of sub-Saharan Africa, Saudi Arabia, and
India, as well as in decedents from the Caribbean, Central America, South America, and
Mediterranean countries.11,12 In the US, the Center for Disease Control and Prevention (CDC)
estimated that SCD affects approximately 100,000 Americans; SCD occurs in 1 out of every 365
African-American births and approximately 1 out of every 16,300 Hispanic-American births.
Furthermore, it is estimated that 1 in 13 African-American babies are born with the sickle cell trait.12
Historically, SCD had a high mortality rate and was considered to be a life threatening illness in
children, with the majority of children not surviving past 3 years.8,13,14 This is no longer true in the
US, as there has been a remarkable improvement in the survival of children with SCD over the past
several decades with over 95% now reaching adulthood.8,15,16 This increased survival can be credited
to the initiation of newborn screening, which allows for early detection as well as parental education
and counseling about disease management and complications, penicillin prophylaxis, Streptococcus
pneumoniae and Hemophilus influezae type b immunizations, and hydroxyurea therapy.4,8,16–18
Unfortunately, the increased survival of adults with SCD has not improved drastically, as their
projected life expectancy remains 20–30 years shorter than the general population.9,16,19

Systemic clinical manifestations

Although SCD is a blood disease, it has damaging effects throughout the entire body and can affect
any organ system. Adult patients with SCD have multiple chronic health problems; with research
showing that 50% of patients who survived to their 5th decade have suffered from irreversible organ
damage as a result of ongoing vasculopathy.9,20 Most of the clinical signs and symptoms of HbSS SCD
are attributed to the chronic anemia and vaso-occlusion that results from the defective RBCs.

Cardiopulmonary complications

Cardiac complications are common in SCD and contribute to the morbidity and mortality of this
disease.21 One serious cardiac manifestation of SCD is left ventricle (LV) dilation. LV dilation is a
S. Alrayyes et al. / Disease-a-Month ] (2017) ]]]–]]] 3

consequence of the chronic hemolytic anemia, causing the LV to develop an increase in cardiac
output while only minimally increasing heart rate, which causes the walls of the LV to thicken and
dilate. The dilation of the LV causes increased systolic wall stress and a compensatory hypertrophic
LV which contributes to diastolic abnormalities and dysfunction.21,22 Patients with SCD who present
with diastolic dysfunction have an increased risk of mortality7,21,22; a study by Redfield et al.
revealed that the even mild diastolic function resulted in a mortality risk that was 5 times higher
than in patients with normal diastolic function.22,23 Pulmonary hypertension (PH) is another serious
complication of SCD that has been associated with LV dysfunction and further increases the risk of
mortality.24 The development of PH is multifactorial; chronic hemolysis and anemia thought to be a
major contributor to its development.9 An early screening tool for PH is to measure the tricuspid
regurgitant jet velocity (TRJV) via an echocardiogram; a TRJV greater than or equal to 2.5 m/s is
highly predictive of PH.9,16,25 Other cardiovascular complications in patients with SCD include
systolic ejection murmurs and cardiomegaly that may develop into congestive heart failure.6,27,28
Acute chest syndrome (ACS) includes a range of acute pulmonary illnesses, it is frequently occurring
and a serious acute complication of SCD. It is a result of vaso-occlusion of the pulmonary vascular
that can cause chronic progressive lung damage.6,28 ACS can rapidly advance to respiratory failure or
death that is why immediate evaluation and treatment are important.26 ACS is the second most
common cause of hospitalization in SCD and is the most common cause of death due to SCD.4 The
clinical symptoms can develop any time and may present as a sudden onset of a combination of
fever, chest pain, cough, shortness of breath, retractions, and rales accompanied by a new pulmonary
infiltrate on a chest radiograph. Children usually present with a fever and upper or middle lobe
involvement, whereas adults are afebrile with multilobe disease. ACS is common in young children
with the most common etiology being a viral respiratory infection, although any infection can be a
trigger.4,26 Asthma is considered a serious comorbidity of SCD as there is a high prevalence of
patients with SCD who are also diagnosed with asthma, and these patients have an increased
frequency of pain episodes, ACS incidents and a higher risk of mortality.4,26 The evaluation of
pulmonary dysfunction and damage is useful to determine disease progression.6,29 The treatment for
ACS is predominantly supportive therapy; it includes supplemental oxygen, incentive spirometry,
antibiotics, bronchodilators, and in some cases transfusions.4,28

Cerebrovascular complications

The central nervous system (CNS) can present with several severe complications as a result of
SCD in the form of cerebrovascular incidents (overt or silent strokes), cranial nerve neuropathies and
vascular malformations. These complications affect nearly 25% of patients with SCD30–32,
approximately 17% of pediatric patients present with some neurologic abnormalities.28 It is
estimated that by 20 years of age around 11% of children with SCD present with overt stroke
symptoms28,33 and 30% will present with silent infarcts.28,34 Vascular involvements can be in the
form of arterial tortuosity, stenosis, occlusion, or aneurysm usually diagnosed by its appearance on
neurologic imaging.30 Arterial tortuosity is considered to be an adaptive response to chronic
hemolytic anemia in patients with SCD. Hematopoiesis is increased to help compensate for the
destruction of RBCs and the constant demand for blood which causes an increase in cardiac output
and a high blood flow velocity, hence arterial tortuosity.30,35 The high blood flow velocity may also
damage the endothelium, contributing to vascular stenosis, occlusion or aneurysm formation.30,36
Cerebrovascular incidents can cause long term impairment of both motor and cognitive functions.
Pediatric patients with SCD that present with psychiatric issues, seizures, poor academic
performance or developmental delay should be evaluated for neurovascular disease.27–29

Musculoskeletal complications

The trademark clinical manifestation of SCD are vaso-occlusive crises (VOC), which is
characterized by acute, severe pain that normally peaks after three or four days but can last weeks.
4 S. Alrayyes et al. / Disease-a-Month ] (2017) ]]]–]]]

Triggers of VOC include acidosis, hypoxia, infection, low body temperature, hypotension, stress and
dehydration.28 It can begin in infancy as dactylitis, with vaso-occlusion of metacarpals and
phalanges resulting in painful swelling of hands and feet.4,16 Treatment of VOCs is predominantly
palliative and includes the use of nonsteroidal anti-inflammatory drugs (NSAID) and opiate
analgesics. Secondary infections from ischemic or avascular bone, as a result from VOCs, make
patients with SCD prone to osteomyelitis.4 Osteomyelitis usually occurs in long bones such as the
femur, tibia, and humerus, but may also affect the maxillofacial bones, particularly the mandible, due
to its relatively poor blood supply. The necrotic bone gives an optimal environment for bacterial
growth, in particular Salmonella and Staphylococcus species. The clinical presentation of osteomyelitis
is prolonged fever, bone pain and swelling at a single site, which is similar to VOC so it is important
to correctly differentiate between the two.4 Patients with SCD can also present with bone marrow
infarcts and avascular necrosis.4,16,28 Several studies have reported that patients with SCD have a
higher prevalence for Vitamin D deficiency, which results in various complications including
secondary hyperparathyroidism, increased bone fracture and increased bone turnover.37–41 Vitamin
D deficiency has also been associated with muscle weakness and persistent musculoskeletal pain.37
Recently an area of increased interest and research is to study the effect of Vitamin D
supplementation on improved pain symptoms.41 The initial results were inconclusive and further
research on the benefits of Vitamin D supplementation and chronic musculoskeletal pain in SCD is
needed.

Splenic sequestration

Children with HbSS are at risk of having splenic enlargement due to the sequestration of RBCs
within the splenic sinusoids. During acute splenic sequestration the spleen becomes acutely
enlarged due to large amounts of systemic blood being pooled into spleen, which results in rapid
circulatory collapse in the form of severe anemia, hypovolemia and possible shock. The patient
having a splenic sequestration crisis will normally present as irritable with a rapidly enlarging
spleen or liver and pain in the upper abdomen, as well as signs of acute anemia (worsening pallor,
generalized weakness, and tachycardia).42 The cause of splenic sequestration is unknown, although
it often follows an acute febrile illness, and can occur without warning. As there is a risk of
reoccurrence the education of parents on detection of splenomegaly can be lifesaving.4,42,43
Infarction of the spleen due to SCD decreases the splenic function and causes children with SCD to be
at an increased risk for infections, particularly by pneumococci and Haemophilus influenzae, which
can result in a fatal bacteremia. In order to help prevent pneumococcal infections, prophylactic
penicillin should be given from 3 months to 5 years. Studies have concluded that the penicillin is no
longer effective after the age of 5 years and can be discontinued, except in children who have had a
severe pneumococcal infection or a splenectomy.4,43

Acute anemia crisis

Another potentially life-threatening complication of SCD affecting children is the development of


an acute aplastic anemia crisis, or transient aplastic crisis. This rapid, drastic decrease in Hb can be
the result of a human parvovirus (B19) infection, which infects the RBC precursors in the bone
marrow and impairs the production of new RBCs.4,43 An aplastic crisis may also develop from other
infections, hypersensitivity reactions, hypoxia, systemic disease, acidosis, dehydration, or trauma.5
Patients with transient aplastic crisis may need a slow, small volume blood transfusion depending
on the severity and clinical status of patient.4

Renal and genitourinary complications

The hypoxic, acidic, and hyperosmolar setting in the renal medulla fosters RBC sickling and vaso-
occlusion, ultimately causing destruction of the vasa recta and the failure to maximally concentrate
urine.4,42 This usually presents in the patient during their first year of life as a fixed urinary output
S. Alrayyes et al. / Disease-a-Month ] (2017) ]]]–]]] 5

(polyuria), resulting in nocturia or enuresis, as well as increased risk for dehydration.4,44 The chronic
vaso-occlusion can cause renal ischemia and papillary necrosis that causes hematuria.4,42 Clinical
manifestations of nephropathy include facial puffiness, loin pain, painless hematuria, leg and
abdominal swelling, frothy urine, anemia, and hypertension. Sickle cell nephropathy can eventually
lead to end stage renal disease, which is indicated by worsening proteinuria, anemia and
hypertension.42
Priapism is a common complication in males with SCD and is defined as an unsolicited,
persistent, painful erection of the penis.4,42 By the 2nd decade 90% of males will have had at least
one episode of priapism and it can occur as young as 3 years.4 The sickled RBCs cause outflow
obstruction (poor venous drainage) and penile ischemia.42 Treatment includes having the patient
urinate, drink water and take a warm shower to stimulate detumescence, as well as at home
administration of oral pseudoephedrine and analgesics for pain. Prolonged priapism that lasts longer
than four hours should seek emergency treatment at a hospital for intravenous hydration, vasoactive
drugs and possible aspiration and irrigation of the corpora cavernosa.4,45

Ocular complications

SCD can have acute and chronic ocular complications. An acute ocular complication of SCD
presents as a sudden change in vision as a result of central retinal occlusion due to sickled RBCs and
is an ocular emergency.44 Chronic vaso-occlusion in the vascular beds of the eye can lead to
ophthalmopathy in the form of comma-shaped conjunctival vessels, iris atrophy, retinal pigmentary
changes, and retinal hemorrhages. Ultimately retinal detachment, as well as vitreous hemorrhage,
may ensue.42,46 Annual eye examinations are recommended for prevention beginning no later than
twenty years of age.46

Hepatobiliary complications

SCD can cause liver damage by intrahepatic trapping of sickled RBCs, transfusion transmitted
hepatropic infections and transfusion siderosis.46,47 Patients with SCD are at an increased risk for
cholelithiasis with bilirubinate (pigment gallstones).4,47 As many as 50% of adults with SCD
experience gallstones, as well as 10% of children aged 2–4 years.4 Acute liver complications from SCD
include acute hepatic sequestration, right upper quadrant syndrome, hepatocellular necrosis with
hepatic failure, and intrahepatic cholestasis.4

Treatment

The mainstay of treating acute complications of SCD include adequate pain control, hydration,
antibiotics, and simple or exchange transfusion as indicated. Hydroxyurea (HU) is the only Food and
Drug Administration (FDA) approved drug therapy for SCD. HU increases the fetal hemoglobin
concentration, a protective factor against SCD, with patients reporting less adverse side effects such
as VOC painful episodes, stroke and ACS.8,48,49 Patients with SCD may routinely receive blood
transfusions to decrease HbS to 430%, suppress HbS synthesis and reduce hemolysis, which in turn
helps in minimizing splenic sequestration, stroke prevention, treating severe anemia, and avoiding
ACS as a result of low PaO2.7,8,50 Albeit helpful, these methods have limitations. Complications can
include volume overload, iron overload, vascular access problems, and possible side effects of
hyroxyurea. The only curative treatment for SCD is a hematopoietic stem cell transplantation (HSCT)
and is only performed on young children with severe symptoms prior to the development of organ
dysfunction. Unfortunately, it is difficult to find HLA-matched donors; this treatment is normally
limited to patients who have an HLA-compatible sibling.7,8 Gene therapy also introduces a new
promising treatment for patients with SCD in thefuture.6,16,51 Gene therapy, particularly addition
therapy, has been studied recently with promising results,51 yet it remains an investigational
approach, perhaps only available in tertiary centers. L-glutamine is another new modality that is
6 S. Alrayyes et al. / Disease-a-Month ] (2017) ]]]–]]]

under investigation, it works as oxidative HbS scavenger. On July 7, 2017, the U.S. Food and Drug
Administration approved L-glutamine oral powder for oral administration to reduce the acute
complications of sickle cell disease in adult and pediatric patients 5 years and older.52 Treatment
with L-glutamine also resulted in a reduction in the number of sickle cell crises, fewer
hospitalizations due to sickle cell pain, fewer cumulative hospital days and a lower incidence of
acute chest syndrome.

Conclusion

SCD is a chronic global health problem. SCD has a wide range of effects on the entire body
resulting in significant morbidities and mortality. As newer modalities of treatment are decreasing
the mortality rates in children, there are more adults living with SCD and its chronic damaging
effects. It is important that every provider treating the patient with SCD understand the disease
process and its numerous chronic complications it imparts on vital organs. Proper interdisciplinary
collaboration between the hematologist and any rendering provider is essential to ensure
appropriate management of the patient with SCD.

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