Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Sickle Cell Anemia

Paul C. Hodges M.D.

To cite this article: Paul C. Hodges M.D. (1965) Sickle Cell Anemia, Postgraduate Medicine, 38:6,
A-75-A-78, DOI: 10.1080/00325481.1965.11696865

To link to this article: http://dx.doi.org/10.1080/00325481.1965.11696865

Published online: 18 Apr 2016.

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Download by: [Monash University Library] Date: 02 July 2016, At: 17:09

Sickle Cell Anemia
Downloaded by [Monash University Library] at 17:09 02 July 2016
IN December 1904 a 20 year old male
Negro professional student, recently arrived
in Chicago from the West Indies, consulted
the late Dr. James B. Herrick because of
malaise, palpitation, shortness of breath, re-
current bouts of fever, and ulcers on his legs.
Herrick, a scholarly and extremely able clini-
cian, found the red blood cell count to be
only 2.8 million, and in fresh drops and
smears he saw sickle-shaped red blood cells
of a sort he had never seen before (figure 1).
He was unable to make a definite diagnosis
but felt strongly that the determining factor
lay in the corpuscles themselves.
The patient returned intermittently during
the following three years and in November
1910 Herrick1 published the case, thus in-
troducing to medical literature the subject of
sickle cell anemia. He said in part, "This case
is reported because of the unusual blood find-
ings, no duplicate of which I have ever seen
described. Whether the blood picture repre-
sents merely a freakish poikilocytosis or is
•visiting Professor of Radiology, University of Florida
College of Medicine, Gainesville. Emeritus Professor, De-
partment of Radiology, University of Chicago, Chicago,
Illinois.
DECEMBER 1965
Radiology
EDITOR: PAUL C. HODGES, M.D.*
dependent on some particular disease, I can-
not at present answer. I report some details
that may seem nonessential, thinking that if
a similar blood condition is found in some
other cases a comparison of clinical condi-
tions may help in solving the problem."
Other cases soon were found and reported,
and by 1923 Taliaferro and Huck2 had estab-
lished the heritable nature of the disease. Two
decades later Pauling8 pinned down the fault
to a congenital defect in the hemoglobin
molecule. Meanwhile there had been con-
fusion over seeming inconsistencies, leading
to the practice of employing the term "sickle
cell anemia" for those cases in which lesions
developed spontaneously and "sickle cell
trait" for those in which the defect was in-
active or latent.
With improved knowledge of the genetics
of the situation, the term "heterozygous sickle
cell anemia" has come to replace "trait" for
those cases in which defective hemoglobin
(hemoglobin S) has been inherited from only
one parent, and "homozygous sickle cell ane-
mia" is used for those in which both parents
have transmitted defects. Formerly it was be-
lieved that only the homozygous form
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 Radiology
FIGURE 1. In vivo sickling in the first case of sickle
cell anemia, reported by James B. Herrick' in 1910.
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Reprinted with permission of the Archives of Internal
Medicine.
brought patients to the clinician, but there is
growing appreciation of the fact that even
the heterozygous form causes trouble when
for any reason the oxygen tension in the
blood is reduced, as by high-altitude airplane
flights or by surgery, particularly under m-
halation anesthesia.
Geographic Dutribution
The gene for hemoglobin S is found in
several foci in the northern part of Africa,
on the island of Madagascar, and particularly
in a broad equatorial belt spanning central
Africa in which the incidence runs as high
as 40 per cent (figure 2). For practical pur-
poses, wherever sickle cell anemia is found
today its presence is indicative of African an-
cestry, although Lehmann4 believes it may
not have arisen in Africa. Possibly in pre-
historic times the gene was introduced from
the East and found an unusually favorable
habitat because in Africa subtertian malaria
was endemic. Particularly in its cerebral form
subtertian malaria kills most of the infants
who become infected, with the exception of
those fortunate enough to have sickle cell
anemia. Those who harbor hemoglobin S are
A-76
not immune to malarial infection, but the
parasites, having entered the blood, are not
able to multiply in the u~ual fashion and as
a result the disease is mild and rarely fatal.
With such a high incidence of the gene it
seems inevitable that the African incidence
of the homozygous form of the disease must
be great and that failure to encounter it clini-
cally in large numbers is explained by the
catastrophic mortality rate seen in homo-
zygous infants.
In the Western world the gene presum-
ably was introduced in the seventeenth cen-
tury with slaves from West Africa, and in
America today it is carried by 8 to 9 per
cent of the Negro population. A few cases
have been reported in presumed non-Negroes
in America, but these persons were of Medi-
terranean stock and therefore possibly from
one of the numerous known foci scattered
from Spain to East Pakistan (figure 2). Dacie5
in his excellent book pointed out that as
knowledge of abnormal hemoglobins grows,
it becomes clear that some cases formerly
thought to be atypical sickle cell anemia were
in fact instances of combinations of more
than one type of defective hemoglobin.
Clinical Features of the
Homozygous Form
The number of victims of homozygous dis-
ease surviving childhood varies with the
quality of available medical care, but even in
the United States few survive to adulthood.
The patients, mostly children, are asthenic,
potbellied and anemic, with red blood cell
counts sometimes as low as 1.5 million but
more commonly 2 million to 3.5 million.
They frequently have leg ulcers and unex-
plained fever and commonly are short of
breath. In males there may be intractable
priapism and in both sexes splenic infarcts
leading eventually to autosplenectomy.
Most characteristic among the symptoms
are recurring crises of abdominal, thoracic
and particularly skeletal pain which are the
POSTGRADUATE MEDICINE
 Radiololf:r
result of thrombosis and tissue ischemia sec-
ondary to agglutination of sickling red blood
cells. All too frequently such crises are mis-
taken for appendicitis, osteomyelitis, etc.,
leading to fruitless and sometimes fatal sur-
gery. The diagnostic problem is complicated
by the fact that in a patient with sickle cell
anemia genuine surgical lesions may develop
either incidentally or secondary to thrombo-
sis. In the few women who reach childbear-
ing age pregnancy poses special hazards.
At physical examination one usually finds
enlargement of the heart, with at least rela-
tive sparing of the left atrium. The liver and
spleen may be small, normal or enlarged, the
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fingers spidery, and the spine kyphotic.
Clinical ~eatures of the
Heterozygous Form
Most of ·those who inherit the defect from
only one parerit go through life unaware of
it unless the defec'i: is discovered by hema-
tologic sampling or until hypoxia precipitates
in vivo sickling. When sickling is induced,
the symptoms and tissue lesions are the same
as in the homozygous form except that they
usually are milder. A patient's first intimation
FIGURE 2. Distribution of
the gene for hemoglobin
S in the Eastern hemi-
sphere. The dark patches
indicate areas is which
the gene is found.
Drawn by Frank S. Moul-
ton from Lehmann's' data.
DE(:EMBER 1965
of his genetic defect may be splenic or pulmo-
nary infarcts, hematuria, or skeletal pain
brought on by the hypoxia of a high-altitude
airplane flight or by surgery or anesthesia.
It has been established that in both forms
of sickle cell anemia detectable ocular hemor-
rhages may occur and it has been claimed"
that even in the absence of actual hemor-
rhage, diagnostic criteria in the conjunctiva
can be revealed by inspection through a 40
diopter ophthalmoscope. In all children of
Negro descent, unexplained hematuria, car-
diomegaly or interstitial hemorrhage should
cause physicians to suspect the presence of
sickle cell anemia.
Laboratory Diagnosis
As in Herrick's original case, direct exami-
nation of a drop or smear of fresh blood is
sufficient to demonstrate characteristic sickle
cells when the disease is of the homozygous
form. When it is heterozygous, it is neces-
sary to deplete the oxygen available to the
red blood cells either by sealing the slide and
setting it aside for a few hours or by adding
a drop of reducing agent. In laboratories
equipped for electrophoresis and the ferro-
A-77
 Radiolo•r
hemoglobin solubility test, 7 a combination
of these two procedures not only confirms the
diagnosis of sickle cell anemia but also dis-
tinguishes between the homozygous and
heterozygous forms.
Mechan.Um and Consequences
oJSickling
The globin of normal hemoglobin is able
to withstand lowered oxygen tension with-
out gross physical change so that even in the
face of severe anoxia red blood cells retain
their normal shape. Such is not the case, how-
ever, with the globin of hemoglobin S. It is
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believed that when the globin is subjected to
reduced oxygen tension and loses oxygen, it
combines with itself to form long, relatively
stiff rods which twist the cells into distorted
shapes, some resembling sickles and others
looking like spiked holly leaves.
Apparently the mere presence of the ab-
normal hemoglobin is well tolerated, but
when sickling occurs the abnormal cells tend
to agglutinate and clump into masses which
plug smaller vessels, causing tissue ischemia
and the usual sequelae. Furthermore, sickled
cells have a relatively short life span so that
anemia develops. As in all chronic anemias,
added work is required of the heart, which
leads to cardiomegaly and, if the vascular
changes secondary to agglutination result in
pulmonary infarcts, the cardiac load increases
and the heart enlarges even more.
X-Ray Findings
The assistance of the radiologist is sought
quite regularly, but his help is at best of a
mere confirmatory nature. He can confirm
the existence of cardiac enlargement, and if
it is desired he can measure the amount of
enlargement and observe changes during the
progress of the disease. He usually will be
able to demonstrate pulmonary infarcts if
they are present, but they have no features to
distinguish them from infarcts not related to
sickle cell anemia. Bone lesions are uncom-
A-78
mon complications, and when they do occur
they differ in no way from the sclerosis and
aseptic necrosis seen in other skeletal insults,
for example, Perthes' disease.
Even in those cases where osteomyelitis is
suspected clinically and the possibility of
sickle cell anemia has not been considered,
radiography is less helpful than might be sup-
posed. Today almost all patients who have
fever and skeletal pain receive antibiotics be-
fore they are seen by the radiologist, so that
he no longer can expect to find typical bone
changes even when genuine osteomyelitis is
present. The fact that a particular skeletal
lesion suspected of being osteomyelitis is not
typical of that disease by no means rules out
that diagnosis and lends only slight support
to the idea that instead of osteomyelitis one
is dealing with a skeletal manifestation of
sickle cell anemia. These matters have been
discussed by Caffey,8 Ehrenpreis and Schwin-
ger,9 Rowe and Haggard,10 and many others.
REFERENCES
1. HEIUUCK, J. B.: Peculiar elongated and sickle-shaped
red blood corpuscles in a case of severe anemia.
Arch Intern Med 6:517-521 (November) 1910.
2. TALIAFERRO, W. H. and HUCK, J. D.: The in-
heritance of sickle cell anemia in man. Genetics
8:594-598, 1923.
3. PAULING, L.: Abnormality of hemoglobin molecules
in hereditary hemolytic anemias. Harvey Lect (1953-
54) 49:216-241, 1955.
4. LEHMANN, H.: Abnormal Haemoglobins-a Sym-
posium. Oxford, England, Blackwell Scientific Publi-
cations Ltd., 1959, p. 202.
5. DACIE, J. V.: The Haemolytic Anaemias: Congeni-
tal and Acquired. Ed. 2. New York, Grune & Strat-
ton, Inc., 1960, pt. 1, pp. 243-263.
6. COMER, P. B. and FRED, H. L. :. Diagnosis of sickle-
cell disease by ophthalmoscopic inspection of con-
junctiva. New Eng J Med 271 :544-546 (September
10) 1964.
7. SUNDERMAN, F. W., }R.: The measurement of ferro-
hemoglobin. In SUNDERMAN, F. W. and SUNDER-
MAN, F. W., }R. (Editors): Hemoglobin; Its Pre-
cursors and Metabolites. Philadelphia, J. B. Lippin-
cott Company, 1964, pp. 109-110.
8. CAFFEY, J.: The skeletal changes in the chronic
hemolytic anemias. Amer J Roentgen 37:293-323,
1937.
9. EHRBNPREIS, B. and ScHwiNGER, H. N.: Sickle
cell anemia. Amer J Roentgen 68:28-36, 1952.
10. RowE, C. W. and HAGGAIID, M. D.: Bone infarct
in sickle cell anemia. Radiology 68:661-668, 1957.
POSTGRADUATE MEDICINE