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Early changes in diet-induced fatty livers of Mice.

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Early Changes in Diet-induced Fatty Livers of Mice'
Department of Anatomy, University of Mississippi School of Medicine,
Jackson, Mississippi
Mice (Taconic Swiss) were fed a high-fat (28% lard), low-protein (8%
casein), lipotropic-deficient diet for 1-90 days. For 21 days parenchymal liposis was
greatest in peripheral and outer middle zones of the lobule. During 21-90 days f a t increased in central and middle zones and decreased in peripheral zones.
Ceroid pigment developed in Kupffer cells within 12 days. During 31-45 days Kupffer
cells coalesced and formed large ceroid globules which increased in size and number
during the 46-90 day period. A reticular fibrosis surrounded the masses of ceroid.
As early as seven days stromal distortion consisting chiefly of compression of reticulum
by fat laden hepatocytes was prominent in peripheral lobular zones. Sinusoids were
also obstructed and dilated by this process. Some became non-functional and were
transformed to fibrous cords. With progressive liposis (after 30 days) irregular stromal
changes developed i n all zones of lobules.
The chronology, pattern and compo- stromal changes have been limited even
nents of the transition of a fatty liver to a after feeding the diets for a year (Ball,
cirrhotic liver have often been subjects of '64; Clower and Williams, '66). These
studies of hepatic liposis produced by feed- several studies were mostly concerned
ing diets that are high in fat, low in pro- with a liposis-fibrosis-cirrhosis sequence
tein and deficient in lipotropic substances produced by feeding a high-fat, lipotropic(Hartroft, '50; Hartroft and Ridout, '51; deficient diets for prolonged periods.
Here feeding a diet similar or identical
Buckley and Hartroft, '55; Ohta, Zaki and
Hoffbauer, '63; Hartroft and Porta, '65; to those used previously produced a
Clower and Williams, '66). Contributing quickly expanding liposis, early stromal
to development of cirrhosis are the fatty changes and exceedingly rapid formation
cysts resulting from massive liposis, large of ceroid pigment in the livers. The TS
amounts of ceroid pigment and the stromal stock of mice fed the diet lacks spontanechanges related to liposis and aggregation ous hepatic lesions that might predispose
of masses of pigment (Blumberg and to rapid and extensive responses to the
Grady, '35; Gyorgy and Goldblatt, '49; diet (Hinton and Williams, '68). The liver
Hartroft, '50; Gyorgy, Goldblatt and Gan- changes considered here as precocious oczin, '59; Hartroft and Porta, '65). Such curred within 3-20 days of feeding the
changes have been considered as due to diet to male and female mice ranging in
continuing and increasing liposis resulting age from 30-48 days at the beginning of
from feeding the atypical diet for three the dietary regimen. The ages corremonths or more (Hartroft and Ridout, '51; sponded to those of weanling-young adult
MacDonald, '62; Hartroft and Porta, '65). rats and mice used routinely in such
The diet considered here is neither de- studies (Williams, '60; Ball, '64).
The onset of parenchymal liposis was
ficient in vitamin E which would greatly
increase ceroid formation nor necrogenic predominantly peripheral lobular rather
which would also stimulate both formation than the expected centrolobular pattern
of this pigment and fibrosis (Casselman, (Hartroft, '54; Meader and Williams, '57;
'51; DeWitt and Schwarz, '59; Porta and Clower and Williams, '66). A concurrent
Hartroft, '63). The responses of strains or quickly sequential formation of ceroid
of mice fed diets identical with the one pigment occurred in macrophages, particuused here are in part genetically condi- larly Kupffer cells, but not in fat-filled
tioned (Ball, '64; Clower and Williams,
1 Supportd by grant HE-07318 and HE-04052 from the
'66). In some strains formation of ceroid National Institute of Health, U.S.P.H.S.
2N. I. H., U.S.P.H.S. Predoctoral Trainee in the
pigment and development of significant Anatomical
Sciences (5TO GM 00287).
ANAT. REC.,161: 23-36.
hepatocytes. Stromal changes within fatty
peripheral zones were earlier and more
extensive than occurred with initial centrolobular liposis (Buckley and Hartroft,
'55; Williams, '60; Clower and Williams,
'66 ).
Animals. The TS (Taconic Swiss)
stock of mice used here has an extensive
life expectancy and lacks spontaneous
lesions other than a low incidence of
lymphatic leukemia in older animals (Ashburn, Williams and Cobb, '63). The postweanling and young adult mice consisted
of 50 males and 104 nulliparous females,
30-48 days of age with 18-30 gm body
weight. Males and females were used
because the former may have an increased
susceptibility to damage by high-fat diets
(Wilgram, Best and Blumenstein, '56; Wilgram, '57). The mice were killed or died
as follows: 1-20 days, 32 mice; 21-60, 62
mice; 61-90, 60 mice. The mortality was
relatively high during 40-90 days because
of the frequency of atrial thrombosis
(Ball, Clower and Williams, '65). Thirtyeight of the 50 males survived for 46-90
days which permitted adequate time for
development of possible sex-limited respon ses.
Housing the mice and feeding the diet
have been described (Ball, Williams and
Collum, '63). To limit oxidation of fats
and fat-soluble vitamins, the experimental
diet was prepared twice weekly and small
amounts of the diet were added to the
feeders as needed.
Mice were weighed weekly during the
course of the experiment and immediately
before autopsy. Mice that died during the
experiment were autopsied soon after
death. The remainder were killed by cervical compression.
Diets. The experimental diet has been
used in other studies and its composition
is as follows:
scribed before (Ball, Williams and Collum,
The diet was not supplemented with a
lipotropic material and is obviously high
in fat and carbohydrate and low in protein. It lacks a high concentration of unsaturated lipids and is not deficient in
vitamin E which is a common characteristic of ceroid-producing diets (Victor and
Pappenheimer, '45; Casselman, '51 ).
Histological methods. These have been
described in detail (Ashburn, Williams and
Arlander, '62; Clower and Williams, '66).
Organs were fixed in 10% aqueous formaldehyde or Lavdowsky's solution. The PAS
method with hematoxylin (PASH) was
used for a survey of tissues (Ashburn, Williams and Cobb, '63). Ceroid was demonstrated in paraffin sections by PAS, acidfast, sudan black B and by the methyl
green technic of Popper, Gyorgy and Goldblatt ('44). Reticular fibers were shown
by a silver method (Gordon and Sweets,
'36) and Mallory's aniline blue method
was used to show collagenous fibers.
Aniline blue did not stain the reticulum of
normal livers nor the argyrophilic fibers
(of fatty livers) described here as reticular. In silver preparations the broad
aniline blue-positive collagenous fibers
were blue-gray while the reticular fibers
were black. A combined PAS-silver
method stained ceroid and reticulum in
the same section. Frozen sections of
formalin-fixed livers were cut at 10 p and
stained with oil red 0 to show lipid. Sections were made through entire lobes of
livers, and the same lobes from each
mouse were studied.
A summary of changes in livers is
presented in table 1
Hepatic liposis. Parenchymal cytoplasm of all three lobular zones contained
small fat droplets within 72 hours. Durgm/100
ing the next eight days liposis remained
fairly constant in central zones where the
greatest concentration was perivenous. In
Casein (vitamin free)
middle and peripheral zones large
Salt mixture no. 2 (U.S.P. XIII)
fat droplets had formed and greatly enL-cystine
larged the cells by 11 days (figs. 1-3). The
Vitamin mixture
pattern of cytoplasmic fat in central cells
The vitamin and salt mixtures were was typically multilocular while that of
completely adequate and have been de- outer midzonal and peripheral lobular
Livers of TS mice fed the high-fat, low-protein, lipotropic-deficient diet
Days fed
Parenchymal fat
Ceroid pigment
Stromal changes (reticular fibers)
Small droplets i n
central zone,
increasing fat with
formation of large
cytoplasmic droplets
in peripheral zone.
In outer middle and peripheral zones
their was compression or condensation
of periparenchymal and perisinusoidal
fibers by fat-filled liver cells and
by obstructed and dilated sinusoids.
Continuation of
above with
formation of fatty
cysts in outer
middle and
peripheral zones.
A shift of
No significant changes
cumulative liposis
from above.
from peripheral to
inner middle and
centrolobular zones.
Increasing liposis and fatty cysts
had distorted further the peripheral
zone. A few fibrous extensions from
portal canals had entered the
peripheral zonal areas of stromal
changes. Changes seen a t 1-11 days
have now involved the entire lobule.
These included short fibrous
extensions from central veins.
No significant changes from above.
Large fat droplets
and fatty cysts in
all zones. Slight
decrease at lobular
1-1 1
Forming in cytoplasm of
Kupffer cells and other
macrophages at 12 days.
Ceroid was dense and
homogeneous in paraffin
Fusion of ceroid
containing Kupffer
cells forming masses of
ceroid with 5-30 nuclei.
The larger globules were
vacuolated or foamy in
appearance. No ceroid
had formed in hepatocytes.
areas was unilocular. Subsequently, 1220 days, the continuing liposis produced
massive enlargement of peripheral zonal
parenchymal cells which was followed by
rupture and fusion of some to form fatty
cysts (Hartroft, ' 5 0 ) .
Fat increased in central and midzonal
areas beginning at 21 days and continued
through the period of study (90 days).
Concurrently, the progressive liposis in
peripheral areas ceased and some decrease
ensued. However, previous massive liposis
in the peripheral zones had produced extensive disorganization in this area which
made it difficult to appraise the situation
in relation to the fat content of individual
cells. By 31 days enlarged, fat-filled
hepatocytes and fatty cysts were present
in all zones including the perivenous
(central) portions of the centrolobular
zone. Thus, during 21-31 days the concentration of liposis shifted from a predominantly peripheral zonal pattern to one
that uniformly involved entire lobules.
Some accentuation of 1 3 0 day
pattern. Irregular pattern of
intralobular fibrosis with increased
perivenous (central) extensions.
Definite fibrosis around masses of
ceroid. Some sinusoids have become
fibrous cords giving a further
impression of increased reticulum.
This transition produced a pattern similar
to the initial central concentration of
lipid, beginning within 24 hours, that has
been considered characteristic of fatty
livers produced by hypolipotropic diets
(Meader and Williams, '57; Williams,
Cardle and Meader, '59; Clower and Williams, '66).
Ceroid pigment. Within 12 days this
pigment developed as homogeneous cytoplasmic deposits in enlarged Kupffer cells
usually located free within sinusoids (fig.
4). Such cells had no lobular zonal pattern of distribution. Ceroid formation had
greatly enlarged these cells. By 31-45
days these swollen, pigment containing
Kupffer cells and other macrophages had
coalesced or fused to form large ceroid
globules which were part of giant cells
with 5-10 nuclei (figs. 5, 6). Obvious
vacuolation in paraffin sections stained
with PAS and with H. and E. indicated
that a lipid component had been removed
(figs. 8, 10). These vacuoles were not
present in frozen sections. Such large aggregates of the pigment were foamy rather
than dense and homogeneous (fig. 9).
Large globules of ceroid had produced obstruction and dilatation of sinusoids (fig.
Cytoplasmic formation of ceroid within
Kupffer cells and enlargement of these
cells as well as their subsequent fusion
to produce large aggregates of the pigment
continued during the 46-90 day period
(fig. 7). Some masses of ceroid contained
as many as 30 nuclei. Large masses of
ceroid formed a boundary between the extremely fatty and minimally fatty cells.
Perivenous, portal and central, accumulations of ceroid were frequent.
Changes in hepatic reticulum. The
rapidly progressive liposis and formation
of ceroid pigment in peripheral lobular
zones was accompanied by local stromal
changes. Within 48-72 hours stromal alterations in the periphery of lobules included compression of periparenchymal
and perisinusoidal reticular fibers by enlarged fat-filled parenchymal cells thus
producing thicker strands of reticulum
(fig. 12). In addition the obstruction, congestion and dilatation of sinusoids had
compressed or condensed small reticular
fibers producing thicker argyrophilic
bands. Similar changes have been described as much later responses in fat
laden centrolobular zones of livers (Meader
and Williams, '57; MacDonald, '62; Ball,
'64; Clower and Williams, '66). The impressive feature here was the peripheral
lobular or portal location in contrast to
centrolobular location (figs. 12, 1 3 ) . The
condition approximated a reversal of the
pattern observed in other stocks of mice
(Clower and Williams, '66). In addition
to the intralobular changes there seemed
to be perivenous extensions of reticulum
from portal canals at seven days (fig. 13).
When these joined the condensed or compressed peripheral lobular reticulum there
was an appearance of beginning portal
reticular fibrosis or an encapsulation of
lobules (fig. 13). An irregular pattern of
intralobular reticular fibrosis with extensions from central veins developed after
peripheral zonal liposis was no longer
dominant (after 30 days) and there were
large amounts of fat throughout lobules
(fig. 14).
Two other responses added to the
stromal changes presented above. Reticular fibers quickly surrounded the large
masses of ceroid produced by fusion of
macrophages containing the pigment (fig.
11). This represented a true increment
and in such sites the reticulum was much
more abundant than that surrounding
fatty hepatocytes. Another source of fibers
appeared to be increased reticulum resulting from obstructed and eventually nonfunctional sinusoids which collapsed. The
obstruction and eventual loss of patency
was due to compression by fatty cysts and
fat-fdled liver cells. Eventually their
mural reticulum appeared as chords or
strands. Similar changes occur in the
fatty livers of rats fed a diet as used here
for long periods (MacDonald, '62).
Age and sex. The changes in livers
and other organs were unrelated to the
sex of mice and to the age (30 or 48 days)
at beginning of feeding the diet.
Other organs. The cardiovascular lesions that appear in TS mice fed a high-fat
diet have been described previously (Ball,
Williams and Collum, '63; Ball, Clower
and Williams, '65). These lesions consisted mostly of atrial mural thrombosis
and myocardial necrosis and calcification.
There were no significant lesions (including ceroid deposits) in kidneys, adrenal glands, lungs, aortas, smooth muscle
or reproductive organs.
Two defects in utilization, transport or
hepatic synthesis of lipid seemed simultaneous or rapidly sequential in the fatty
livers. One was the cumulative liposis in
parenchymal cells, and the other a rapid
formation of ceroid in Kupffer cells. Under
the conditions that existed such metabolic
faults are not new, but the intralobular
pattern was different and the processes
were much more rapid or premature than
described before. Previously, particularly
in mice, the initial and predominant liposis has been clearly centrolobular with a
subsequent spread toward the periphery
of lobules (Buckley and Hartroft, '55;
Meader and Williams, '57; Williams, Cardle and Meader, '59). Here the reverse oc-
curred. The early and concentrated centrolobular liposis is only specific or consistent when the dietary fat contains a
broad spectrum of lipids such as in lard
or butter. When saturated compounds are
excessive in such diets initial liposis is
peripheral lobular, considerably reduced
and little ceroid is ever formed (Williams
and Oliver, '61). One explanation for the
unexpected and very rapid pattern of
liposis may be a genetic component in
TS mice that favors extensive and rapid
hepatic liposis. Certain other stocks of
mice have a susceptibilty to hepatic
liposis that is unrelated to lipotropic deficiency (Fenton, Dowling and Mershon,
'54). Lending support to such an explanation is the marked susceptibility of the
TS stock to production of cardiovascular
injury by the same diet as used here (Ball,
Williams and Collum, '63; Ball, Clower
and Williams, '66). Excluding effects of a
high intake of fat and lipotropic deficiency
protein deficiency in itself favors peripheral lobular liposis (Shils and Steward, '54;
Best, Hartroft, Lucas and Ridout, '55).
Formation of ceroid pigment in Kupffer
cells accompanied this rapid and predominantly peripheral zonal liposis. In
studies with other stocks of mice this pigment was not produced for 16 weeks or
more even when the diets were deficient
in vitamin E which should accelerate and
increase formation of ceroid (Victor and
Pappenheimer, '45; Hartroft and Porta,
'65). Formation of this pigment did not
occur for nine weeks in rats fed diets
which should be much more ceroidogenic
than the one used here (Norkin, '66).
Necrosis hastens ceroid formation but
such injury did not occur here and the
most altered elements, fat-laden parenchymal cells, were not the sites of pigment
formation (Hartroft and Porta, '65). In
the present study this early and extensive
development of ceroid differed from that
in nearly identical dietary studies where
the pigment was formed in both parenchyma and macrophages at a much
later time (Hartroft and Porta, '65).
Both the lipotropic deficiency and a
genetic susceptibility may have contributed to the initially peripheral predominant pattern of liposis and also to the
rapid formation of ceroid pigment. Later
(21-45 days) the full influence of the
lipotropic deficiency seemed dominant
thus producing a change to the typical
central zonal concentration of liposis in
the lobule.
A conclusion that initial stromal
changes are due to pressure of large fat
filled hepatocytes or fatty cysts agrees with
those of Hartroft ('50, '54) and Popper,
Schaffner, Hutterer, Paronetto and Barka
('60). These large cells and cysts also
obstruct and dilate sinusoids and which
eventually eliminates some of them as
channels and converts them into fibrous
cords (MacDonald, '62). None of this
was a significant increase in fibrous tissue
although the distortion of stromal architecture suggested an increment in reticulum. A real increase consisting of numerous reticular fibers occurred adjacent to
the enlarging masses of ceroid pigment.
Ashburn, A. D., W. L. Williams and T. R. Arlander
1962 Comparative action of cortisone, androgens and vitamin Bi? on body weight and incidence of disease in mice. Anat. Rec., 144: 1-17.
Ashburn, A. D., W. L. Williams and F. R. Cobb
1963 Cardiovascular, hepatic and renal lesions
i n mice receiving cortisone, estrone, and progesterone. Yale J. Biol. Med., 35: 329-340.
Ball, C. R. 1964 Actions of betaine, carnitine
and choline on the pattern of hepatic liposis in
mice fed a high-fat, low-protein diet. Anat. Rec.,
149: 677-689.
Ball, C. R., W. L. Williams and J. Collum 1963
Cardiovascular lesions i n Swiss mice fed a high
fat-low protein diet with and without betaine
supplementation. Anat. Rec., 145: 49-60.
Ball, C. R., B. R. Clower and W. L. Williams 1965
Dietary-induced atrial thrombosis in mice. Arch.
Path., 80: 391-396.
Best, C., W. Hartroft, C. Lucas and J. Ridout 1955
Effects of dietary protein, lipotropic factors and
re-alimentation of total hapatic lipids and their
distribution. Brit. Med. J., I : 1439-1444.
Blumberg, H., and H. Grady 1935 Production of
cirrhosis of the liver in rats by feeding low protein, high fat diets. Arch. Path., 34: 1035-1041.
Buckley, G., and W. Hartroft 1955 Pathology of
choline deficiency i n the mouse. Arch. Path.,
59: 185-197.
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and histochemical properties of substances resembling ceroid. J. Exp. Med., 94: 549-562.
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of the C strain. Am. J. Anat., 118: 391-410.
DeWitt, W. B., and K. Schwarz 1958 Multiple
dietary necrotic degeneration of the mouse. Experientia, 14: 28-30.
Fenton, P., M. Dowling and J. Mershon 1954
Relation of dietary fat level to fatty livers i n
several strains of mice. J. Natl. Can. Inst., 15:
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method for silver impregnation of reticulum.
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Gyorgy, P., H. Goldblatt and M. Ganzin 1959
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cells and in lipodiastaemata preceding experimental dietary cirrhosis. Anat. Rec., 106: 61-87.
1954 The sequence of pathological
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liver and cirrhosis. Ann. N. Y. Acad. Sci., 57:
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Hartroft, W., and E. Porta 1965 Ceroid. Am. J.
Med. Scs., 250: 324-345.
Hinton, D., and W. L. Williams 1968 Hepatic
fibrosis associated with aging i n four strains of
mice. J. Geront. (in press).
MacDonald, R. 1962 Pathogenesis of nutritional cirrhosis. Arch. Int. Med., 110: 424434.
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deficiency in the mouse. Am. J. Anat., 100: 167204.
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Ohta, Y., F. Zaki and F. Hoffbauer 1963 Fatty
cirrhosis in the rat. Am. J. Path., 42: 729-741.
Popper, H., P. Gyorgy and H. Goldblatt 1944
Fluorescent material (ceroid) i n experimental
nutritional cirrhosis. Arch. Path., 37: 161-168.
Popper, H., F. Schaffner, F. Hutterer, F. Paronetto
and T. Barka 1960 Parenchymal fibrogenesis:
The liver. Ann. N. Y. Acad. Sci., 86: 1075-1088.
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upon the occurrence of ceroid pigment i n dietary
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C, Central vein
P , Portal vein
P A S H , Periodic acid Schiffs reagent method with hematoxylin, as applied
to paraffin sections
Ret, Silver method for demonstrating reticular fibers applied to paraffin
S B f , Frozen section stained with Sudan b k c k to show lipid
S B p , Paraffiin section stained with Sudan black to show ceroid
All figures show livers
Central zones contain small multilocular fat droplets. Droplets i n
outer middle and peripheral zones are very large and for the most
part represent a unilocular arrangement of fat. The range i n size of
droplets and the pattern shown here occurred within 72 hours. x 100.
Protal zone.
Characteristic pattern of liposis during 3-20 days. S B f .
x 400.
Central zone. x 400.
Arrows indicate initial formation of ceroid pigment in cytoplasm of
Kupffer cells. This occurred within 12 days PASH. x 500.
Beginning a t 31 days masses of ceroid were formed by fusion of
Kupffer cells and other macrophages whose cytoplasm contains the
pigment. S B p . x 100.
Jack L. Wilson, Allen D. Ashburn and W. Lane Williams
Continued aggregation or fusion of ceroid containing macrophages to
form large masses of pigment SBp. x 100.
Large masses of ceroid and a site, lower left, of fusion of several cells
filled with the pigment. There are also three apparently single Kupffer
cells greatly distended by ceroid. Numerous fatty cysts are shown.
Note absence of ceroid within fatty parenchyma and cysts. SBp.
x 350.
Obviously vacuolated or foamy ceroid. PASH.
Numerous masses of ceroid showing some evidence of vacuolation.
S B p . x 175.
Jack L. Kilson, Allen 1). Ashburn and W. Lane Williams
Encapsulation of masses of ceroid by reticular fibers. Other
reticular fibers in the area have increased in number or been condensed or have merged. P A S H , Ret. x 400.
Fat filled parenchyma and the congested and dilated sinusoids have
compressed and distorted the reticular fibers of peripheral zones
which are the sites of maximal liposis as early as one day. This
condition developed within seven days and continued for three to
four weeks. The distorted area of reticulum seems to link two portal
areas in figure 12. In figure 13 this linkage has a pattern of
pseudoencapsulation of a lobule. A central vein is in the center of
figure 13. Ret. x 100.
Some slight and irregular increase of perivenous and intralobular
reticulum occurrins as liposis involves entire lobules. Upper vessel
is a central vein and the larger one at lower right is a portal vein.
Ret. x 100.
Jack L. Wilson, Allen D. Ashburn and W. Lane Williams
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