T H E AMERICAN JOURNAL OF CLINICAL PATHOLOGY
Vol. 37, No. 1, pp. 65-74
January, 1962
Copyright © 1902 by The Williams & Wilkins Co
Printed in U.S.A.
WHIPPLE'S DISEASE IN A 3-MONTH-OLD INFANT
WITH INVOLVEMENT OF THE BONE MARROW
Department
C H A R L E S H . AUST, M . D . , AND E D W A R D B. S M I T H , M . D .
of Pathology, Indiana University School of Medicine, Indianapolis 7,
In 1907 G. H. Whipple36 described the
first example of the disease which now bears
his name. The condition is characterized by
gradual loss of weight and strength, stools
that are excessive in neutral fat and fatty
acids, indefinite abdominal signs, and a peculiar multiple arthritis.12 In addition to the
pathologic changes observed in the lamina
propria of the small intestine and in the
mesenteric lymph nodes, there is also involvement of all of the major organ systems
of the body. The reticuloendothelial cells, including the tissue macrophages, contain
characteristic particles which react positively
to the periodic acid-Schiff technic (PAS).
Black-Schaffer2 in 1949 demonstrated histochemically that this nonsudanophilic material was a glycoprotein; thus, the emphasis
shifted from the study of the sudanophilic to
the nonsudanophilic material in Whipple's
disease. As a result of the observations of
Sieracki and associates,28-30 the presence of
characteristic PAS-positive particles has become accepted as virtually pathognomonic
of Whipple's disease.
Of the approximately 75 acceptable
instances of Whipple's disease in the literature, all but 4 have occurred in persons over
the age of 25 years. 5 ' 2 l - 3 6 Of these 4, 3 have
been patients of more than 9 years of age,
and only 1 has been observed during infancy. Whipple's disease is rare and is extremely rare in infancy. It is our purpose in
this paper (1) to describe the occurrence of
Whipple's disease in a 3-month-old male
infant, with widespread systemic involvement, including the reticuloendothelial system and the bone marrow; (2) to recom-
Indiana
mend the bone marrow as a site for biopsy;
(3) to reaffirm that Whipple's disease is a
systemic disease; and (4) to suggest that
Whipple's disease may be a storage disease
with some enzymatic defect.
DIAGNOSIS BY MEANS OF
BIOPSY
Following the original report, 20 years
elapsed before a second instance of Whipple's
disease was described,3 and 30 years passed
before a case was diagnosed antemortem.
The appearance of the characteristic lesions
in the lymph nodes, other than abdominal
ones, was reported by Korsch18 in 1938.
Rutishauser and associates,26 in 1948, described the presence of granulomatosis in the
spleen and hilar lymph nodes. Oliver-Pascual
and associates,20 in 1947, and Hendrix and
co-workers,16 in 1950, reported the first and
second cases diagnosed during life, by means
of biopsy of a mesenteric lymph node.
Upton,33 in 1952, was the first to report widespread distribution of the characteristic
macrophages containing PAS-positive particles in the portal triads, in perinephric fat,
and in the vegetations found on the valves of
the heart. Fisher and Whitman 9 noted cervical lymph nodes containing cells resembling
those described by Upton, but, because they
were less PAS-positive, they concluded that
it was probably not possible to diagnose
Whipple's disease by means of biopsy of a
peripheral lymph node. Pruite and Tesluk,23
in 1955, suggested that it might be possible
to confirm the diagnosis of Whipple's disease
by means of biopsy of a peripheral lymph
node, and in 1959 Chears and associates7
described the first case diagnosed in this
manner, thus sparing the necessity for
laparotomy. Recently, 4, 13 Whipple's disease
has been diagnosed by means of transoral
biopsy of the small intestine. In addition, rebiopsy after therapy has also been described.14 The first instance reported in a
Negro was diagnosed in 19G0 by means of ex-
Received, April 26, 1901; revision received,
J u l j ' 28; accepted for publication October 4.
Dr. Aust is Resident-Instructor in Pathology,
and also Clinical Fellow of the American Cancer
Society. D r . Smith is Professor and Chairman,
D e p a r t m e n t of Pathology.
66
Jan. 1962
WHIPPLE S DISEASE
67
F I G . 1. Gross specimen of jejunum after fixation in 10 per cent formalin. Note the minute granular
projections in the mucosa, which lend a velvety appearance to t h e surface.
animation of tissue obtained in the same
manner.31 We suggest that the diagnosis may
also be made by means of biopsy of the bone
marrow.
REPORT OF CASE
The patient was a 3-month-old white
male infant, who was referred to the Indiana
University Medical Center because of
"failure to thrive." The infant was a product
of a full-term' normal pregnancy, and the
birth weight was 6 lb. and 6 oz. At the time
of admission the weight of the infant had increased to 7 lb. and 4 oz. The infant was pale
and emaciated, and had loose skin, with
scant subcutaneous fat and poor turgor. The
lymph nodes were not palpable. The anterior
fontanel was depressed, and the eyes had a
sunken appearance. Results from the examination of the heart and lungs were within
normal limits. The abdomen was distended,
and the liver and spleen were palpable.
Laboratory findings. At the time of admission urinalysis revealed 10 to 15 pus cells per
high-power field, and subsequent urinalyses
were within normal limits. The hemoglobin
level varied between 7 and 12 Gm. per 100
ml. of blood. The white blood cell count was
22,000 per cubic millimeter of blood, and a
"shift to the left" was present. Repeat counts
of the white blood cells were within normal
limits during the 12-day hospitalization. The
levels of chlorides in the sweat and alkaline
phosphatase in the blood were within
normal limits. The serum electrolytes of the
blood were normal except for the carbon
dioxide-combining power, which was reduced
to 12.5 mEq. per liter. The total nonprotein
nitrogen level of the blood was normal. JVO
pathogenic bacteria were isolated from the
stool cultures. A roentgenogram of the chest
was interpreted as being within normal
limits. A roentgenogram of the abdomen indicated the presence of an increase in gas in the
68
Vol. 87
AUST AND SMITH
intestines, but there was no evidence of
mechanical obstruction.
Hospital course. The child was fed a
formula of evaporated milk. On the sixth day
of hospitalization the child began having 5
to 7 loose, yellow, foul-smelling stools per
day. On the ninth day of the hospitalization,
bleeding from needle-puncture wounds occurred and was difficult to stop. At this time
the prothrombin level of the plasma was 10
per cent of normal. The hemoglobin level of
the blood decreased to 7 Gm. per 100 ml. The
infant received transfusions of whole blood,
each in the amount of 10 ml. per pound of
body weight. The hemoglobin level increased
to 12 Gm. per 100 ml. of blood. The infant
was dehydrated, lethargic, and in shock. He
died after 12 days of hospitalization.
Summary of <yross autopsy findings. The
weight of the body was 2950 Gm. There was
evidence of dehydration and emaciation,
manifested by loss of subcutaneous tissue
turgor, depression of the anterior fontanel,
and sunken eyeballs.
The outstanding gross features were
limited to the abdominal cavity. The liver
and spleen were enlarged. The mucosal
surfaces of the duodenum, jejunum, and
ileum contained many minute, granular,
yellow projections, which lent a velvety appearance to the surface (Fig. 1). The colon
was not remarkable. Serositis was not
present.
The lymph nodes of the mesentery were
tan, firm, and enlarged; the largest one was
3.5 cm. in diameter. On cut section a tan,
homogeneous appearance was present, and
no follicles were visible (Fig. 2). Porous
lymph nodes were not observed.
The bone marrow seemed to be cellular,
and varied from red to tan. The lungs were
tan and firm. The remainder of the organs
did not manifest significant pathologic
changes. The central nervous system was not
examined.
Histologic Study
F I G . 2. Gross section of ti mesenteric lymph
node after fixation in 10 per cent formalin. Note
the homogeneous appearance and effacement of
the normal architecture owing to engorgement
with lipid-laden and protein-laden macrophages.
Materials and methods. The tissues were
fixed in a solution of 10 per cent formalin,
Zenker's solution, and absolute ethyl alcohol.
Alternate histologic sections were prepared
with hematoxylin and eosin and by means of
the periodic acid-Schiff (PAS) technic,19 with
and without diastase digestion. Formalinfixed tissue was stained for fat, utilizing
Sudan IV stain. Stains for fat in the bone
marrow were accomplished by means of cutting through a piece of marrow which had a
peripheral zone of cartilage to hold it together. The alcohol-fixed material was
stained by means of the Best carmine
technic.
Observations. The following, long-recognized microscopic features of Whipple's disease were observed: sudanophilic material in
tissue macrophages in the lamina propria of
the small intestine (Fig. 3); in the mesenteric,
periaortic, and mediastinal lymph nodes; and
in the lungs, liver, spleen, thymus, adrenal
glands, perirenal tissue, stomach, large intestine, and bone marrow. In addition, the
macrophages located in these sites contained
droplet-like homogeneous particles varying
in size from 1 to 3 yu, and varying in shape
Jan. 1962
W H I P P L E ' S DISEASE
69
Fici. 3 (upper). Histologic section of jejunum prepared by means of the periodic acid-SchifT teclinic
Note the villi which are club-shaped because of the accumulation of lipid and protein in the lamini
nrnpria. The epithelium of the villi has been lostj iiuiii
from Liiift
this JJUHIJIIIUI
postmortem
X ou.
30.
propi
u«in sspecimen.
p c c i n i u i i . .A,
a n - " " ' «••««•>i-<><-i
.,n-;^i; acid-SchifT
IFici. 4 (lower). Histologic section of bone mlarrow
prepared i^«
by •««».>•«>
means «f
of n...
the periodic
techhnic. The arruios point to particles of PAS-positi
~ : tive material in the cytoplasm of reticuloendothelial
cells. X 1082
70
ATJST AND
from round to polygonal (Figs. 4 and 5). The
particles reacted positively to the periodic
acid-Schiff technic and were resistant to
diastase digestion. A few macrophages containing these particles were also observed in
the interstitial tissue of the kidneys, ureters,
and urinary bladder. The Best carmine technic failed to reveal the presence of glycogen
in any of the macrophages.
The large macrophages containing both
lipid droplets and PAS-positive particles
were the predominant cells in areas of pathologic change. These cells were prominent in
the lamina propria of the small intestine, and
they, in combination with lipid debris, were
responsible for the configuration of the
"club-shaped" villi of the small intestine
(Pig. 3).
The lymph nodes were not porous, but did
contain large macrophages in the peripheral
sinuses and in the sinusoids (Fig. 6). Many
of these macrophages contained the dropletlike particles which reacted positively to the
periodic acid-Schiff technic.
In the lung this type of macrophage was
present in the alveoli, in the interstitial connective tissue, and in the alveolar septums.
The Kupf'fcr cells of the liver contained lipid
and particles which reacted positively to the
periodic acid-Schiff technic. In addition,
there was advanced fatty metamorphosis of
the liver. The spleen contained similar
macrophages in the sinusoids and in the subcapsular region. The macrophages in the
spleen contained not only lipid and PASpositive granules, but also hemosiderin. The
bone marrow was hypercellular with many
large reticuloendothelial cells containing lipid
and the PAS-positive particles (Fig. 5).
DISCUSSION
The occurrence of the gross and histologic
features of Whipple's disease in a 3-monthold male infant is indeed rare. There are
certain morphologic features present in
adults that are absent in children with this
disease. These features are: (1) serositis, (2)
porous type of lymph node, and (3) granulomatosis of the mesenteric lymph nodes.
We believe that the absence of the serositis
can be explained on a temporal basis. The
usual example of Whipple's disease is seen in
SMITH
Vol. 87
a man more than 25 years of age, and in our
patient (an infant) there was only a brief
period for pathologic changes to develop. It
is postulated that there is an inborn defect in
the metabolism of the reticuloendothelial
cell, perhaps the lack of an enzyme; therefore, in adult patients with this disease, the
findings may represent pathologic changes
that have progressed over a period of years.
The porous type of lymph node and the
granulomatous reaction are absent, in our
opinion, because the lipid and protein are
confined within the reticuloendothelial cells.
Thus, the large "lakes" of fat and fatty acids
in the lymph nodes of adults are not present
ininfantswiththisdisease. The porous lymph
node is only one of the types of lesions seen
in adult patients with Whipple's disease. The
nonporous homogeneous lymph node that is
seen in adults is the type of lymph node that
was present in our patient.
The morphologic difference between the
droplet-like PAS-positive particles observed
in the tissues of our patient and the PASpositive "sickle-form" particles described by
Sieracki and co-workers28-30 is owing to the
fact that the "sickle-form" particle is seen
well only in preparations that are made from
imprints of tissue or lymph nodes before
fixation. When the particles are seen in
sections 5 /u thick, the exact shapes of the
individual particles are indistinct, and the
oblique and transverse sectioning of the particles causes apparent variations in form.
The absence of sickling of the PAS-positive
particles in our example of Whipple's disease
may also be related to the young age of the
patient, in whom there was only a brief opportunity for storage and crowding of the
particles in the cells of the reticuloendothelial
system.
We attribute the fact that the dropletlike PAS-positive particles were not found in
all of the organs of the body to the young
age of our patient, and to the short time
available for dissemination of the particles.
The thoracic duct was not identified and
dissected in our patient at the time of
autopsy because the pathologic changes were
not recognized as those of Whipple's disease
by the prosector. Careful dissection of the
thoracic duct or main lymphatic duct in the
F I G . 5 (upper). Histologic section of 2 reticuloendothelial cells in a vein of a section from liver.
The section was prepared by means of the periodic acid-Schilf technic, and the arrows point to the PASpositive particles in the cytoplasm. (The cytoplasm also contained a large amount of lipid, which stained
with Sudan IV.) X 2040.
F I G . G (lower). Histologic section of the peripheral sinus of a lymph node. Note the large vacuolated
cells containing lipid and protein (see arrow). Hematoxylin and eosin. X 938.
71
72
Vol. 37
AUST AND SMITH
past has not revealed obstruction to be the
cause of the accumulation of lipid and
glycoprotein in the mesenteric lymph
nodes. 3 - 2 l ' 2 4 ' 2 7
The pathogenesis and etiology of Whipple's disease are unknown. The disease has
usually occurred in men above the age of 25
years, although well documented cases have
been reported in women. Various theories regarding the pathogenesis of the disease have
been advanced over the years. That the disease is an abnormality of fat metabolism was
suggested by Whipple36 in 1907, Gaertner 10
in 1938, Korsch18 in 1938, Apperly and
Copeley1 in 1943, and Reveno24 in 1950.
Casselman and co-workers6 suggested that
Whipple's disease could be an abnormality
of lymphoid tissue resulting in excessive production of a glycoprotein complex. Jones and
associates,17 as well as Peterson and Kampmeier,21 have suggested that Whipple's disease is a so-called collagen disease, but histologic studies do not support this. Plummet1
and colleagues22 also postulated a close resemblance to the collagen diseases. Gross
and associates11 have suggested that heredity
may play a part in this disease. Warner and
Friedman34 have called attention to the lipogranulomatosis in lymph nodes and pointed
out the resemblance to the lesions seen in
patients with Boeck's sarcoid. Sieracki and
associates28"30 have emphasized the involvement of all of the major organs of the body,
including the central nervous system, by the
characteristic lesions of Whipple's disease. In
1957 reticuloendotheliosis of the skin in
Whipple's disease was reported.25 Dick8 described a reticuloendotheliosis in the mesenteric and peripheral lymph nodes and the
subcutaneous fat. Taft and associates32 believe that the defect is a proliferation of
mucoprotein-producing reticuloendothelial
cells maximally concentrated in the lymphatic system of the small intestine.
Haubrich and colleagues15 agree in essence
with Taft's conclusions and, after extensive
histochemical and electron microscopic
studies, conclude that the disease may
represent a storage disease. They postulate
that Whipple's disease may be produced by
mutant reticuloendothelial cells proliferating throughout the body.
Whipple's disease may be a storage disease. Further evidence of this is the presence
of lipid and glycoprotein in the reticuloendothelial system, bone marrow, and
virtually every organ of the body in our
patient, a 3-month-old infant. It is similar
to other storage diseases, but involves glycoprotein instead of lipid or glycogen.
The cause of the pathologic changes in
Whipple's disease remains unknown. If the
disease proves to be of the storage type, it
is possible that the cause is a defect in the
metabolism of the reticuloendothelial cells.
SUMMARY
1. An instance of Whipple's disease occurring in a 3-month-old male infant, with
involvement of the major organs of the
body, including the reticuloendothelial system and the bone marrow, is described. This
is the second case, to our knowledge, of
Whipple's disease reported at this early age.
2. The bone marrow is recommended as an
additional site for biopsy in order to aid in
the diagnosis.
3. The occurrence of PAS-positive dropletlike particles in macrophages of the reticuloendothelial system and all major organ
systems reaffirms the systemic nature of
Whipple's disease.
4. It is suggested that Whipple's disease
is a storage disease primarily involving protein. Whether or not the accumulation of
the PAS-positive material in tissue macrophages and reticuloendothelial cells is a
process of phagocytosis or abnormal metabolism of these cells remains to be proved
conclusively.
SUMMA.RIO IiV lXTERLlNGTJA
1. Es describite un caso de morbo de
Whipple incontrate in un infante de tres
menses de etate. Le major organos del
corpore esseva afficite, incluse le systema
reticuloendothelial e le medulla ossee. Intra
le limites de nostre informationes, isto es le
secunde caso de morbo de Whipple reportate
in un patiente de si juvene etate.
2. Le medulla ossee es recommendate
como si to additional pro le biopsia a objectivo diagnostic.
3. Le occurrentia, in macrophagos del
Jan. 1962
73
WHIPPLE'S DISEASE
systema reticuloendothelial e de omne le
major organos, de particulas guttettiforme
a positivitate pro PAS constitue un reaffirmation del natura systemic de morbo de
Whipple.
4. Es formulate le concepto que morbo de
Whipple es un morbo de magasinage, concernente proteina primarimente. Si o non le
accumulation de material a positivitate pro
PAS in macrophagos tissular e cellulas
reticuloendothelial es un processo de phagocytosis o de un anormalitate metabolic
remane a determinar.
12. G U T M A N , A. B . : In C E C I L , R. L., and L O E B ,
R. F . : Textbook of Medicine, E d . 9. Philadelphia: W. B . Saunders Company, 1950,
p. 090
13. HARGROVE M . D., J R . , V E R N E R , J . V., J R . ,
PATRICK,
R . L., AND R U F F I N ,
J. M.:
In-
testinal lipodystrophy without diarrhea.
J. A. M . A., 173: 1125-1128, 1960.
14. H A R G R O V E , M . D . , J R . , V E R N E R , J . V'., S M I T H ,
A. G., H O R S W E L L , R. R., AND R U F F I N ,
J.
M . : Whipple's disease: report of two cases
with intestinal biopsy before and after
t r e a t m e n t . Gastroenterology, 39: 019-024,
1900.
15. H A U B R I C H , W. S., W A T S O N , J . H . L., SIERACKT,
J. C : Unique morphologic features of
Whipple's disease. Gastroenterology, 39:
454^168, 1900.
BLACK-SCHAFFER,
10. H E N D R I X , J . P . ,
B.
WITHERS,
R.
W.,
AND H A N D L E R , P.
Acknowledgments.
T h e authors are indebted
Whipple's intestinal lipodystrophy: report
to M r . Paris C. Johnson and to Mr. Joseph M .
of four cases and discussion of possible
Demma, D e p a r t m e n t of Illustration, Indiana
pathogenic factors. Arch. I n t . Med., 85:
91-131, 1950.
University Medical Center, for preparation of t h e
17. J O N E S , C. M . , B E N S O N , J . A., J R . , AND R O Q U E ,
photomicrographs.
A. L . : Whipple's disease: report of a case
with special reference t o histochemical
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SMITH
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