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772 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 773

clinical practice because of nonmedical reasons. Increases in HbF and retinopathy, as have angiopoietin-1 and -2 and von Willebrand fac-
257
transfusions occasionally hasten healing of leg ulcers. 258 tor. Pigment epithelium derived factor, an angiogenesis inhibitor, is
increased as well, especially in nonviable “sea fans.” 274–276
Hepatobiliary Complications Proliferative sickle cell retinopathy may differ from other prolifer-
Chronic liver abnormalities in SCD are frequent and of different etiolo- ative retinopathies in that spontaneous regression of neovascularization
gies that include vasoocclusion, transfusional iron overload, pigmented can occur in up to 60 percent of cases. 277,278 The Jamaican cohort study
gallstones with bile duct obstruction, acute or chronic cholecystitis, reported an annual incidence of 0.5 cases per 100 HbSS subjects versus
viral hepatitis, and cholestasis. 259,260 Common clinical manifestations 2.5 cases per 100 HbSC subjects. Prevalence was greater in HbSC sub-
include right upper quadrant pain, fever, hepatomegaly, nausea, and jects as well, with a 43 percent rate in the third decade versus 14 percent
vomiting. Bilirubin levels from chronic hemolysis are usually not above for those with HbSS. However, there was a 32 percent incidence of spon-
261
6 mg/dL, with a majority of it being the indirect fraction. Because taneous regression. Irreversible visual loss occurred only in 2 percent
some degree of aspartate transaminase elevation is seen with hemolysis, of HbSC subjects up to 26 years of age observed at time of the study. 277
279
alanine transaminase elevation is a more accurate marker of liver injury. Central retinal artery occlusion is rare in HbSS disease. Con-
Vasoocclusion involving the hepatic sinusoids was seen in 39 per- junctival vascularity is decreased in SCD patients compared to controls
cent of patients in one study, while previous reports of vasoocclusion with further decreased vascularity and decreased conjunctival red cell
involving the liver, termed acute sickle hepatic crisis, has been reported velocities during vasoocclusion. 280–283
in 10 percent of patients. The differing prevalence is the result of varying An orbital compression syndrome characterized by fever, head-
criteria used to include biochemical and clinical abnormalities. Acute ache, orbital swelling, and visual impairment secondary to optic nerve
262
hepatic sequestration crisis characterized by a rapidly enlarging, tender dysfunction can occur in SCD. Orbital marrow infarction is a common
liver and hypovolemia is akin to splenic sequestration but much rarer. cause. 284
It requires prompt treatment with red cell transfusion. Severe intrahe- All patients with sickle hemoglobinopathies should have a yearly
patic cholestasis with serum bilirubin levels as high as 100 mg/dL is ophthalmology examination beginning in childhood. The examination
a catastrophic situation needing exchange transfusion for resolution; should be carried out by an ophthalmologist and should include slit-
synthetic liver function is lost as characterized by low serum albumin lamp examination of the anterior chamber and detailed retinal visual-
and coagulation protein abnormalities; renal impairment may occur. ization including a fluorescein angiography in addition to visual acuity.
A more benign form of cholestasis has been described, which resolves The evaluation and treatment of proliferative sickle retinopathy is
with conservative measure. 263–268 complicated by the fact that spontaneous regression may occur. Laser
Chronic hemolysis results in an increased burden on the heme cat- photocoagulation remains the most commonly performed proce-
abolic pathway leading to increased unconjugated bilirubin and forma- dure for this finding. Traumatic hyphema needs urgent optical refer-
tion of pigmented gallstones. The incidence of gallstones increases with ral because increased sickle red cells can cause obstruction of outflow
age, with a reported prevalence of 50 percent at 22 years of age. 269–271 The channels, resulting in acute glaucoma. This vascular obstruction may
number of uridine diphosphate (UDP) glucuronosyltransferase 1 family cause decrease in retinal and optic nerve perfusion causing further
(UGT1A1) promoter (TA) repeats (the polymorphism associated with visual problems. Unresolved vitreous hemorrhage and retinal detach-
Gilbert syndrome) is strongly associated with increased incidence of gall- ment may need surgical intervention. Exchange transfusion to keep
stones and bilirubin levels while coinherited α-thalassemia (Chap. 48) HbA at more than 50 percent is recommended. Central retinal artery
decreases bilirubin levels in patients with SCD. Laparoscopic chole- occlusion needs urgent exchange transfusion and an ophthalmology
272
cystectomy is recommended in symptomatic patients with cholelithiasis. consultation. 277,285–287 Orbital compression syndrome is treated with glu-
The treatment of asymptomatic patients with positive findings on abdom- cocorticoids with the addition of antibiotics if concomitant infection
inal ultrasonography is more controversial. In the Jamaican cohort study, cannot be ruled out. 126
only 7 percent of patients with positive ultrasonograms had symptoms
suggestive of biliary tract disease and needed a cholecystectomy. How- Splenic Complications
ever, patients in the United States appear to be more symptomatic, with Functional asplenia defined as impaired mononuclear phagocyte sys-
288
the majority of gallbladders removed after only a positive ultrasonogram tem functions in the spleen occurs in 86 percent of infants with SCD.
have pathologic evidence of cholecystitis. Asymptomatic patients with It is defined by the presence of Howell-Jolly bodies and absence of Tc
269
99m
negative screening ultrasonograms should be observed; however, timing (99m-technetium) splenic uptake, even in the presence of a palpable
and frequency of screening has not been standardized. spleen. Slow blood flow in the red pulp of the spleen sets the stage for
increased red cell sickling. Repeated splenic infarctions lead to “autosple-
Ophthalmic Complications nectomy.” As a consequence, patients are prone to microbial infections,
The microvasculature of the retina with relative hypoxemia facili- especially with encapsulated microorganisms such as S. pneumoniae,
tates “sickling” akin to several other vascular beds. Microcirculatory Haemophilus influenzae, and Neisseria meningitidis. Hypertransfusion
obstruction occurs followed by neovascularization and arteriovenous early in childhood, prior to age 7 years, may lead to reversal of func-
aneurysms. Hemorrhage, scarring, and retinal detachment leading to tional asplenia. Marrow transplantation and hydroxyurea have resulted
blindness are the sequelae. Changes occur at the periphery, thereby in reversal of functional asplenia in some older subjects. Splenic seques-
sparing central vision at earlier stages. The term sickle cell retinopathy tration occurs in young children. 289–293
encompasses nonproliferative and proliferative changes.
Nonproliferative changes include “salmon-patch” hemorrhages, Management during Pregnancy
peripheral retinal lesions termed “black sunbursts,” and iridescent spots, Differing morbidity and mortality rates have been reported in pregnant
whereas neovascularization is characteristic of proliferative changes, women with SCD, some of which is attributed to geographic location
giving a pattern of vascular lesions resembling a marine invertebrate and access to healthcare. Although the CSSCD data showed low rates
and is termed as “sea fans.” 273 of pregnancy loss and mortality, other studies have shown an increased
Increased levels of plasma and intraocular vascular endothe- mortality of 10 to 100 orders of magnitude greater as compared to non
lial growth factor have been documented in proliferative sickle cell -SCD patients. 285–290 Preterm delivery occurs in 30 to 50 percent of SCD

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