Case 4 -
Sickle Cell Anemia
University of Virginia
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The patient, a 42-year-old African-American male, underwent
a cholecystectomy for cholelithiasis. During the surgical procedure, a liver biopsy was performed.
[Figure 4-1 (H&E, 200X), Figures 4-2, 4-3, 4-4 (H&E, 400X), Figure 4-5 (Trichrome, 200X), Figure
4-6 (Prussian blue, 200X).
Case 4 - Figure 1 - Sections of the liver biopsy show the characteristic sickled hepatocytes within congested and dilated sinusoids. (H&E, 200X and 400X, respectively)
Case 4 - Figure 2 - Sections of the liver biopsy show the characteristic sickled hepatocytes within congested and dilated sinusoids. (H&E, 200X and 400X, respectively)
Case 4 - Figure 3 - Erythrophagocytosis by Kupffer cells is identified. (H&E, 400X)
Sickle cell anemia
Sections of the liver biopsy show the
characteristic sickled erythrocytes within congested and dilated sinusoids. Kupffer cell hyperplasia and
focal extramedullary hematopoesis are identified. A trichrome stain demonstrates perivenular fibrosis.
Markedly increased (4+) iron stores are identified on the Prussian blue stain, with the iron present in
both hepatocytes and Kupffer cells and distributed throughout all zones of the hepatic lobules.
Hemoglobin, which transports oxygen from the lungs to the tissues and carbon dioxide from
the tissues back to the lungs, is composed of a tetramer of globin chains. The normal adult form of
hemoglobin consists of a pair of a chains (141 amino acids long) and a pair of b chains (146 amino acids
long). Accordingly, the major normal adult hemoglobin (HbA) has the structure
a2b2. The conformation of the globin chains changes reversibly depending on the
state of oxygenation.
Hemoglobinopathies are disorders that affect the structure, function, or production of hemoglobin, and
there are five major classes of hemoglobinopathies: structural hemoglobinopathies; thalassemias;
thalassemic hemoglobin variants; hereditary persistence of fetal hemoglobin; and acquired
hemoglobinopathies . Sickle cell diseases, which are a type of structural hemoglobinopathy, are
disorders in which the erythrocytes undergo sickling when they are deoxygenated and thereby produce
prominent clinical manifestations . These diseases are caused by a mutation that changes the amino
acid sequence of a globin chain, and this in turn, alters the physiologic properties of the variant
hemoglobins. In the case of sickle cell hemoglobin (HbS), a mutation in the b-globin gene changes the
sixth amino acid from glutamic acid to valine (a2 b26 Glu
ŪVal). Sickle cell anemia, the prototype sickle cell disease, is the homozygous state for the
sickle cell gene (HbSS). This discussion will focus on the sickle cell anemia.
Hemoglobin S occurs with greatest prevalence in tropical Africa, where the heterozygote
frequency ranges between 20%-40% of the population depending on the specific geographic area. It is also
relatively common in the United States; HbS occurs in heterozygous form in approximately 8% of
African-Americans and in homozygous form in 1 in 400 of this population.
Due to the alteration in primary structure, molecules of HbS have a strong tendency to
polymerize reversibly into microtubules when deoxygenated . These aggregates of microtubules stiffen
the cytoplasmic membrane and increase the cytoplasmic viscosity of the affected erythrocytes, resulting
in the characteristic sickle shape. Importantly, because of these changes, the sickled cells loose the
pliability needed to transverse capillaries. In addition, repetitive cycles of sickling and unsickling
results in severe injury to the cytoplasmic membrane of the affected erythrocytes; due to this membrane
injury, these "irreversibly" sickled erythrocytes are abnormally adherent to the endothelium . This
feature, in conjunction with the decreased cellular pliability, as well the complex interplay of a
variety of non-erythrocyte-related factors, results in repeated episodes of vaso-oclusion, as the rigid,
adherent sickled erythrocytes occlude and clog capillaries and small venules . This vaso-occlusion,
in turn, results in tissue ischemia and microinfarctions.
The clinical manifestations of sickle cell anemia are vast and are beyond the scope of
this discussion. In sum, they are dominated by lifelong hemolytic anemia, sequelae of repeated of
vaso-occlusive events in a wide variety of organs and tissues (which often results in pain and ischemic
type tissue damage), and increased susceptibility to infections, particularly S.
pneumoniae, which in part is related to absent splenic function (that is often due to
autosplenectomy). Typically patients achieve a steady state of relative well being that is periodically
interrupted by a crisis, which may be of a vaso-occlusive, aplastic, sequestration, or hemolytic type.
The disease is readily suspected on the basis of the clinical features in conjunction with the
characteristic erythrocyte morphology on a peripheral blood smear. The diagnosis is confirmed by
hemoglobin electrophoresis along with an assay for hemoglobin sickling, solubility, or oxygen affinity,
such as the sickle solubility test. The diagnosis is usually established in childhood, but occasional
patients, often compound heterozygous states, do not develop symptoms until the onset of puberty,
pregnancy, or adult life .
Hepatobiliary Manifestations of Sickle Cell Anemia
Liver and biliary tract dysfunction are common complications of sickle cell disease and
result in a variety of clinicopathologic syndromes, as described below. In sickle cell anemia patients,
the typical clinical setting in which a liver biopsy is performed is during cholecystectomy, though
occasionally a biopsy is performed for evaluation of hepatomegaly and/or liver test abnormalities .
Characteristic Morphologic Features in the Liver
In sickle cell anemia, morphological changes in the liver are common, and they are
unrelated to as whether or not the patient is having a sickling crisis at the time of the biopsy
The morphologic features are a direct result of the pathophysiologic consequences of the disease. The
relatively anoxic environment of the hepatic sinusoids results in intrahepatic erythrocyte sickling.
Accordingly, aggregates of sickled erythrocyte are particularly prominent within the perivenular zone,
producing sinusoidal dilatation and congestion, which may be panlobular, or on occasion, results in
peliosis. The finding of dilated sinusoids congested with sickled erythrocytes is the "hallmark"
morphologic feature of sickle cell disease in the liver. Futhermore, the aggregates of packed sickle
cells may cause vaso-occlusion, which in turn, may cause local ischemic necrosis. This may result in
fibrosis and possibly eventual cirrhosis (see below).
Other characteristic morphologic features include Kupffer cell hyperplasia and erythrophagocytosis by
Kupffer cells. This latter feature may be particularly evident in patients without a spleen (either due
to elective splenectomy or autosplenectomy), in which case the liver then serves as the major site of
erythrocyte destruction. Also, hemosiderosis often is present, and the extent is a function of the
number of transfusions that the patient has received. The increased iron stores are within both
hepatocytes and Kupffer cells and are distributed throughout all lobular zones. Other morphologic
features may include perivenular fibrosis, extramedullary hematopoesis, and foci of hepatocyte necrosis
randomly distributed throughout the lobule.
Both portal and lobular inflammation, predominantly lymphocytic, may be seen in the setting of sickle
cell anemia. From the published literature, however, it is difficult to determine whether this
inflammation is due solely to the disease. These patients are at risk for transfusion-acquired viral
hepatitis, and the reported series were either prior to or include at least some cases prior to available
testing for hepatitis C (and in some instances, hepatitis B). From a practical perspective, if hepatitic
features are present and well developed, the possibility of a co-existent hepatitis, such as hepatitis C
or autoimmune hepatitis, merits consideration.
Sickle cell anemia is characterized by increased total bilirubin, which may be either
predominantly of the conjugated (direct) or unconjugated (indirect) type. This increase in bilirubin is
present not only in symptomatic patients but also in those patients with steady state disease who are
asymptomatic in regard to the liver . In addition, in steady-state disease, typically there is only
minimal to mild elevation of transaminases . More markedly elevated transaminases merits
investigation of other possible etiologies of liver disease, such as a co-existent viral hepatitis.
Alkaline phosphastase also may be mildly to moderately elevated, but higher elevations may be due to
biliary tract obstruction (secondary to choledocholithiasis, which is relatively common in this patient
population, as described below) or a vaso-oclusive crisis involving the bones rather than pathology of
Development of Cirrhosis
In patients with sickle cell anemia, it is difficult to precisely determine the incidence of cirrhosis
that is due solely to this disease, as these patients are at risk for transfusion-acquired viral
hepatitis. In some series, cirrhosis has been observed in up to 16% to 29% of patients with sickle cell
disease . However, most of these studies were performed before the availability of sensitive tests
for hepatitis B and hepatitis C; as such, co-existent viral hepatitis cannot be excluded as a
contributory factor for the development of cirrhosis in these cases. Within this limitation, however, it
does appear that in some cases, sickle cell anemia alone may result in progressive fibrosis and
cirrhosis. In this setting, both repeated episodes of microinfarctions as well as hepatic iron overload
have been proposed as major causative factors of the chronic liver injury and cirrhosis.
Acute Hepatic Failure in Sickle Cell Disease
Acute hepatic failure is an uncommon, though in some cases, catastrophic, complication of sickle cell
Also known as sickle cell intrahepatic cholestasis or sickle cell hepatopathy, it is
characterized by sudden onset of right upper quadrant pain, progressive tender hepatomegaly, extreme
hyperbilirubinemia, in some cases significantly increased transaminases, and variable degrees of hepatic
dysfunction, such as prolonged prothrombin time. The few reports of the liver pathology in this setting
note the characteristic hepatic morphologic features of sickle cell anemia (as described above) as well
as marked cholestasis, hepatocyte ballooning, and in some cases, centrilobular necrosis. The clinical
outcome is variable, and the condition often is fatal.
Other Hepatic Syndromes and Lesions
Acute hepatic crisis is one of the most common acute hepatic complications of sickle cell anemia
. It is characterized by right upper quadrant pain, increasing jaundice, hepatomegaly, mild to
moderate elevation of transaminases, and elevations in bilirubin that seldom exceeds 15 mg/dl (257
mmol/l). It has a short, self-limited clinical course and typically does not come to liver biopsy.
Hepatic sequestration also may occur in sickle cell anemia, though it is uncommon . It is results
from the massive sequestration of red blood cells in the liver and presents as acute hepatic enlargement
associated with rapidly falling hemoglobin. Typically, a liver biopsy is not performed.
In patients with sickle cell anemia, hepatic infarction may occur rarely, and it is usually caused by
hepatic artery rather than portal vein occlusion
There is also an increased incidence of liver
abscesses in patients with sickle cell anemia ; in some cases, this may be due to secondary infection
of hepatic infarcts. Focal nodular hyperplasia, possibly related to local ischemia from sickle cell
thrombosis, has been reported in children sickle cell anemia
In addition, nodule regenerative
hyperplasia of the liver has been reported in an adult with sickle cell disease . Sickle cell
thrombosis, with subsequent local ischemia, is proposed as the pathologic mechanism in this setting, as
Cholelithiasis in Sickle Cell Disease
There is high incidence of gallstones in patients with sickle cell disease, though the exact incidence
varies between studies
As in other hemolytic states, the gallstones in sickle cell disease
are typically of the pigmented (calcium bilirubinate) type and result from increased bilirubin
excretion. Children under 10 years are reported to have a 14% incidence of cholelithiasis, and
gallstones have been found in children as young as 6 years. The incidence increases with patient age,
and approximately 50% to 70% of adult patients have choleliathisis. Studies vary as to whether or not
this incidence is higher in women than men. Choledocholithiasis also is common in adult patients with
sickle cell anemia, with a reported incidence of 14%. The increased incidence of choledocholithiasis in
sickle cell anemia predisposes this patient population to biliary tract obstruction and its associated
sequelae. Therefore, hyperbilirubinemia in patients with sickle cell anemia may be due not only to
hemolysis or intrahepatic causes but also to extrahepatic etiologies such as choledocholithiasis.
Ultrasound of the biliary tract is highly accurate in the evaluation for the latter possibility .
The morphologic findings in the liver biopsy typically can be readily attributed to sickle cell anemia
when the complete clinical history is provided and/or the characteristic sickled erythrocytes are
identified within the hepatic sinusoids. The diagnosis may become more challenging in the absence of the
complete history or when the sickled erythrocytes are overlooked in the biopsy specimen. As such, it is
useful to include a brief evaluation of erythrocyte morphology in the routine review of all liver
If the complete clinical history is not provided or the presence of sickled erythrocytes is
overlooked, the presence of sinusoidal congestion and dilatation raises of differential diagnosis of
entities characterized by this feature . In addition, the hepatic hemosiderosis raises the
differential diagnoses of entities in which increased hepatic iron stores dominate the histologic
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