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THE RESTORATION OF THE LIVER

By Joshua Lederberg, A.S. V~12 USNR.

A thesis in partial fulfillment of the requiraments for the course
in cuysiolozy. College of Phys‘oiana and Surgeons, Columbia Univer~
sity. 13 May 1945.
‘Tha main factor that determines the weight of the heart,
kidneys, and liver protein is the amount of work these organs
are required to verforn,..' (Walter & Addis '39). This doctrine,
while a convenient mnemonio for the experimentally discovered -
fact of the regulation of the size of these and other orgens,
unfortunately provides no insight into the meohanisns by which
this weight regulation 4g accomplished. The atudy of the phenome
enon of compensatory hypertrophy of the thyroid and adrenal glands
has resulted in the discovery in the last 15 years of the elaborate
mechanisu by which the gize and function of these organs are under
the endocrine control of the pituitary body. It is hoped that a
similar study of the regulation and restoration of the liver might
Lead to some elucidation of the means by which this 4mportant
orgen is maintained in its typical proportion to the body as 4
whole, and to the more fundamental problem of the control of growth
processes in general. | -

The operation of this control isa perhaps nowhere more dram
atically illustrated than in the phenomenon of the restoration of
the liver after partial surgical ablation. ‘This process is the
more immediate subject of this review.

This history of liver restoration, and the polemies on
certain histological aspects of it have been reviewed elsewhere in
gome detail; space does not permit a review of this interesting

nistorieal study. (podwyesozky '86, Fishback '29,) |
| The anatomical arrangement of the lobes of the rat liver
permits of the ready removal of 70 t. 3% ; the median and left
lateral lobes constituting this proportion of the total liver mase-
« 2

Within 10 days after partial hepatectomy, the rest (1.e., the in«
 $aot liver mass) growa to reach the original weight of the entire
liver! (Higgins & Anderson '3la.) In the rabbit, 20% of the Liver
oan reatore the whole (ponfick 190). Fig.1,2 from Hieggine and
Anderson's and Brues! (Brues et al 36a) data respectively demonstrate
the rate of weight restoration of the liver. The most generally
used basis of measurement is the ratio of liver-weight to body |
weight, This standard assumes that the ‘normal growth! of the organ
is an automatic proseas that is independent of the phenomenon under
atudy, a conception that 1s perhaps erroneous. The variation of
‘the body weight over the duration of most experiments or ag a result
of oneration is too slight, however, to vary the picture of what
happens.

These observations indicate that tere is a ravid increase
in weight after operation which 1a negatively accelerated, the wt.
dnoréase tapering off rather markedly after 5-7 days. In Higeinb!
serics, the wet-weicht owershoots the normal level, while the dry~-
weight remains on a plateau at the normal weight. Brues, however,
report a slightly lower plateau. These differences are probably
not statistically aignificant. While Higgins claims that there 1s
a oyclic variation in the rate of restoration, the data again are
not sufficiently refined to allow of such interpretations of dew
Viatione of individual points on the weight~-time curves, although
the results as a whole are unassailable. | .

The bugaboo of all growth measuremente is the problem of
what index to use, While perhaps most convenient, weight changes
do not adequately demonstrate our intuitive concept of growth.

The weipht of the liver is extraordinarily labile under different
~3-=

dietary conditione, and hae furthermore a highly variable fot content.
(Addis et al '36, Luck '36) Furthermore, calculations from data
on Liver weights and fat content under different dietary conditions
-{noluding oholine deficienoy (Handler & Bernheim '45) indicate that
the deposition of one gm. of fatty acid 1s associated with an ine
Grease in liver weight of three grams. ¥et, the deposition of fat
be not ordinarily regarded as 'growth'. The role of the liver as
the ‘commisariat'of the body' makes partioularly agdifficult an estim-+
‘ation of what constitutes ite gwowth. A criterion that has been
used is celleincrease, a process that is, as we shall see, not ale
ways correlated with weight-inorease.
Bruee, et al ("36) have made direct studies on cell number in restor=
ing rat livers. Their results are summarized in Fig. 3. except
that there ig no appreciable increase in cell»enumber during the first
_Gay = after overation, the cell increase parallels the weight restor-
“ation of the liver. In starved animals, however, the weigit plateaus
at about the second day, whereas the cell-increase ig not appreciably
“aitferent from the fed controls. (fig. 3) This suggests the greater
| ‘guitability of thie oriterion. In this paper analyses are reported
which indicate that the material taken in during the first day of
restoration ta low in nitrogen. Thig material hag been shown to
‘be Lpoid {Handler and Bernhein 43) Female rats, in partioular
are prone to ‘develop fatty livers after partial hepatectomy. The
basis of this condition has not been established. Brues réports
that a fatty diet retards cell-restoration well below that of faated
controls, a fact of some Olinical significance. (Ravdin et al 43.)
“The importance of diet in restoration will be discussed in more dou

‘tail below.
o~ & aw

To explain the phenomenon of restoration, Higgins, Mann
and their soworkers at the Mayo Foundation have suggested that the
‘portal blood plays an important role. On the assujmtion that the
influx through the mesenteric arteries le relatively constant,

*the volume of blood which is delivered to any hepatic remannant
efter partial hepatectomy determines largely the extent of its
restoration.! (Higgins, et al., '32.) They promose that the dimine
ution in the siae of the liver inureases the flow to the remant ,
which is responsible for the hyperplasis. More recently, Mann ('40)
has suggested that the presence of some substance in the portal
blood only, or vascular pressure in the Sinusoids may be factors. |
‘In support of this hypothesis, the Mayo group have reported @ nume
ber of interesting experimenta. }

Stevhenson ('33) placed a loose ligature around the rortal
vein in the rat, partially obstructing if, and determined the weight
restoration after artial hepatectomy. Only two-thirds of the amount
reported above by Higgins and Anderson was found. Where Llarse cole
lateral vessels were apparent, the extent of restoration was normal.
From this one may conclude that a normal portel clroulation is neo»
essary for restoration. In dogs, partial hepatectomy two months
after the establishment of an Eck fistula resulted in no signs of
weight restoration. The effect of the Eck fistula in the dog is a
-§0% atrophy of the liver with central fatty accumilation,. (Mann et
al '3la) | | — =
7 - The venous anatomy of the domeatic fowl 1s unique in the

:
Coe ts

existence of a larce ensstonausig between the portol and coval ~
drainsges via thacolocygeoemesenteric vein, Studies on this animal

indicate a slighs, 4f any, degree of waight restoration after the
«» Bo

partial hepatectomy. (Higgins et al 33.) This 4s ascribed to the
drainage away from the portal vein through this anstomosis of excess
blood after partial hepatectomy. If the vena cava is ligated above
the renal veine, the extent of weight restoration is increased con=
. giderably (60%) over controls. In fact, the ligation alone, which
would deliver an increased volume of blood to the liver is reported
to induce a gize inorease in four cases. These studies were, unfore
tunately, based on weight determinations alone, subject to the crit-
4oisms above. Furthermore, transference of concepts from the fowl
to the mammal 46 not immediately Justified. In conflict with these
results, (Crechowitsch '36). complete restoration in the fowl and
dove after partial hevateotomy haa been reported but the published
data here are partioularly inadequate.

Finally, Mann has succedded in estebligshing an open portale
caval lateral anastomosis in the dog. (Mann '40). In five cases, wt.
restoration was reported to be less than in the control animala.
the basis of oompsrigon is, as usual, liver weight, body weight, and
the assertion ig made that for 200 animals, this ratio was 0345.

The veriance of this mean value is not given, however, so that statq
istical evaluation of his resuite is impossible.
. It would be most desirable to have a demonstration in the

rat of the effect of an increased hevatio portal blood flow on .
nitotic rates or celleinorease in the liver. Apparently for obvious
technical reasons, a reverse Eck fistula has not been reported for
this (email) animal. | |

| While the Mayo group hag undoubtedly demonstrated a close
relationship between the weight of the liver and an intact portal
_ Gupply, the latter being a neosessary condition for weight restoration
» 6 =

measurements on blood flow in partially hepateatomized animals heve
not been recorted, and the proportional inorease to the hepatic rem-
nant is entirely suppositicus. Ponfick (290) observed the temporary
mesenteric congestion that follows partial heratectomy, but rejeota
this as a cause of restoration on the basis of its transience. On
the other hend, the liver ig no passive container of blood, but Wakim
and Mann ('42) have themselves demonstrated, by the tranglumination
technique of Knisely, that circulatory activity in the liver 1s
intermittent, and apparently under some degree of active control.
Thermo-Stromuhr measurements indicate a recirrocal relation between
flow in the portal vein and hepatic artery, and that the liv r my
alternately store end discharge blood, (Grindley, Herrick & Mann 41.)
An elabor:- te 'sluice-valve mechanism has been shown to regulete portal
flow in the liver (Deysach '41.), and the hepatic flow can be influ.
enced by sympatho= and parasympethomimetic Grugs (Wakim '44) as well
as by symmethetio stimulation (Griffith and Emery '30) In view of |
these researches, the statue of the liver circulation in pertial-
- hepatectomized animale, and its relation to restoration must etill
be regarded as unsettled. Further studies alao show the unreliabile
ity of weight data. | a
| As a basis for a hypothesis of liver restoration, its mode
“4fteation and simulation by experimental techniques must be considered.
Such influences as diet and hormonal regulation have been studied.

In inanition, the kiver loses more weight proportionally
then any other organ, or than the body as a whole. ‘While it has
been suggested that this represents a utilizetion of the liver mate
erlalg for the rest of the organism, experiments have been reported

which may indloate that the situation is not so simple. (Jackson '15
Addis, et al '36)

In the rat, the weight of the liver can be reduced to
40 a of ite normal size by fasting (10 days). If a partially hep}
atectomiged animal is fasted, the remnant, in this 30 %, inoreases
to the 40 % of the intact, starved animals. These authors conclude
that the reduction in mass of the liver in stravation is due orimare
Aly to a reduced liver requirement in the starved animal. The
partioular funotion of the liver that is to be maintained is not
{ndicated, nor the mechanism by which a changed ‘functional demand!
ean modify liver size. (Rous & McMaster '24.) Brues et 91 (loc.olt.)
have shown that the cellular increase is not diminished in cshese
atarved enimals, so that the functional demand that controls liver
gize and that controle cell-increase are not indentical. This mule
tiplicetion of hypothesis perhaps calis for Oosam's Razor. Roust
results can perhaps be interpreted by postulating that cartial hepe
atectomy induces some stimulus to hepatic growth, irrespective of.
nutritional condition. In order to demonstrate that the relation of
Liver size to portal flow is not comparable to ita dependence on
food intake, cytological studies or cell counte must be revorted
from rat livers in which the portal blood haa been diverted, and
this has not been done. .

. The liver oan be enlarged by varicus dietary doniitions,
euch ae casein refeeding (Luck '36). 5ince no particular frection
of the liver has been shown to be inoreased, it hag been assumed
that an actual ‘protoplasmic! inerease has ocourred, hile cell
eounts have not been made, 4t apvears that there is a hypertrophy |
rether than a hyperplasia of the liver cells. Weight increases: are
most marked on feeding dried liver or kidney, which hss been
wo T«

interpreted as due to nucleic acid content, a conclusion of vart-
4oular interest in view of Marshek's recent observations (see below.)
(Welter and Addig '39)

The optimun diet for liver weight restoration 1s one ‘high
in caloric content, high in carbohydrate, adequate in protein, Bup~
plememted with vitamins and low, but not lacking in f-t.' (Mann '43-).

Other local conditions can modify the rate of restoration,
Of these, the effeot of obatructing the hepatic duct 1s perhaps of
the grectest olinical interest. Ligation of the-duct in the rat
(where there is no gall biedder) leads to an enlargement of the liver,
which may subside if the potency of the duct is reestablished with
solution of the ligature. Otherwise the aninels do not survive
longer than four weeks. If partial hepatectomy is verformed immed-
feately after the obstruction, there is an apparent hypertrophy, even
more racid then in normally restoring llvera. Microscople examinae
tion reveals, however, thet this hypertrophy is cue to a distension
with RBC and retained bile. ‘This 18 accompented iby fibrotic changes,
a petholosical picture accepted by some as ‘biliary cirrhosia. !
qrere 4g no evidence of cell-proliferetion as in normal restoration.
(Hisgins & Anderson '33.) In the dog, survival after cholaecysteoe
tomy end obstruction is muoh longersprobably indefinite if the animal
is properly nursed, One to seven weeks leter there are no merked -
histolosical changes, but restoration does not occur (on ae weight
basis) after partial resection. However, the presence of an increased
number of mitotio figures in the parenchyma is reported. Concurrently
there was apparent engorgement of the ginusolds. (Mann '3lb.) In
this animal there is evidently less damacre to the liver parcnchyma

after obstruction then in the rat. The nature of this ‘damage’ is
not sufficiently well understood to allow this effect to be fitted
in to any of. the theories of liver restoration. Theat biliary obstruce
tion does limit the'growth potentialities’ of the liver parenchymal
calle is indicated by work on transvlents. At best, autotransplanted
liver cells do not survive very well. Although the graft may take
for a tice, the parenchymal cells typically disintegrate efter 1-2
weeks, leaving a branching network of bile-duct cells which may.
persist considerably longer. (Cameron '36, Loeb '18, Otsuka '39.) If
the transplants are taken from livers that have already been obstructed,
survivel of the greft 1s very muoh curtailed, on obstruction of more
than three days being critical. If the liver is obstructed efter
the groit 1g taken from the liver, the resulting jeundice doss not
influcnce the hepetio trensplant. (Cameron '25.) Bile duct celis
proliferste in all circumstences,
Expepimental cirrhosig induced in the rat by acministre-.
tion of CCl4 ner os algo limits the extent of restoeration, few
restorative signs being seen if a fibretic atrophy hes elrosdy oG-
curred. (Mann et al '3le.) Thet the rechanism of liver restorstion
has broken down in the cirrhotic animal is fairly clear, since in
the early course of experimentel oirrhocis, destruction by chemicals
of masses of liver parenohyma is following by their reple.cenent by
the mitotic proliferation of und:meged cells, a nrocess that is
analagoug to restoration after surgical resection. When thig rew
placement does not occur, cirrhosis is established, (Schultz et al
493, Mann'43). The newly restored liver 4a less sensitive to the
administration of CHCl, and CCly, and more sensitive to Phosvhorus
poisoning than is the normal ret liver. Tha pethology of the lesions

is however the same. (Andargon '53, Lacquet '33, Love '35.)
-~ 9m»

Sone attempts have been made to demonstrate an endocrine
control of restoration, but they have so far been quite inconclusive.
The effects of hypochysectomy have been investigated by the Heyo
workers in relation to weight restoration, and by others with celle
counts, in the rat. (Higging & Ingle '39, Franseen et al'33.) The
weight restoration is markedly diminished by hyponnysectomy verformed
1 week prior to the liver operation. Thia may be largely a metter
of appetite. Hypophysectomized animals regenerated ‘27° of the
weight of the liver which regenernted in the adequately fed controls. !
Rnimals which were neired-fed with the hypophysectomized rata rerene
erated '40;: of that which regenerated in those animals which te as
‘much as they wished,' The significence of this difference is not
clesr, but it is epvarent that enorexia is the major factor in Gime
Inighiug welght restoration. Frenseen restricted the diet of his |
controls so thet thelr weicht was ccomperatie to the hypophysectome
ized enimcle, end found no significant dirference in the weight
restoretion. Furthermore, mitotic rates and cell-counts were not
variable between hypophysectcmized, semi-starved and normal rots
after hevatecony. The results of these independent observetiong
demonstr:te thet, unlike the control in other glands such ae the
thyroids and gonads, the hypophysis does not play an importent |
role in meGiating the compensatory hypertrophy of the diver. | One
week, however, is not long enough to allow involution of the >ite
uitary-controlled glands in the rat, so that Lhese experimants do
not disallow endocrine control by other organs.

In contrast to the lack of effect of removal of the pitue
itary, the administration of pituitary extracts has been shown ta

cGeuse £ merked increase in the size of the liver. here is sone

evidence that this 1s mediated through the thyroid. The administration
- 10 -

of a grow thehormons preparation, < units daily for 1-16 days led to
an increase in liver wieght, absolutely and pr portionately of z2bout
20%. This wes accompanied by increase in Callecount of about 18%,
which wes atetistically significant. Feeding influenced the size of
the liver cells, and of the total liver wieght, but did not affeot
Liver cell number. The magnitude of this increase was not such a8
gould be reflected in mitotic rates, and colohicine was not used.
Tis observation if {mportant because it demonstrates thet a ‘true
growth' has taken place, and that the inerensé in liver weight is
hyverplastic, somparcble to the regenerating liver. Since cell-in-
crease will occur in hypophysectomized restoring livers, this efirest
of APL either plays no vole in normal restoraticn, or plays on sone
other ‘step in the canin or events that controls restoration. (Lee &
Freeman '40.)

Fraenkel-Gonrat (et. al. '42) have examined the effects
of a series of rakatively purified pituitory preparations on the
Liver weight of hypophysectomized fats. ine freotions ugeu azd
lactogenic, ACT, Somatotrophic, Thyrotrophic, ICSh and PO activities.
Of these fractions, only the growth and thyrotropnic hormone active
ones caused significant ancreases in liver weicht. The grovth hormone
fraction, furthermore, had an hepatotrophic activity compureble to
its thyrotroohie action, 40 that these authors rostulate that the thy-
roftrophic action,is that which is responsible for the increase in
liver <eight. The N contents of the hynertropnied Livers did not
very eignificantly from the controls, 'so that they must be regarded
as actual changes 4n the amount of liver substance. '

Observations reported incidentally to tne renotrophic affects”

of pituitery extracts (Selye & Nielgon '44) indicate thet the prolonged
administration of orude alk. extracts cf APl over a period of two
months can induce an absolute increase of liver size over controls
of almost 100%, and relative to body weight of 40 %. The oyto~
logical basig of this increase was not studied. While there are
very nurercue reports of changes in tisceral size under pituitary
variation, they will not be reported here beceuse of the ambiguity
of their interpretation in the absence of cytological information.

| In view of the specificity of TTH in stimulating liver
dnorease, the role of the thyroid gland in restoration seems promis~
ing. Attempts to ascertain the effects of hyperthyroid# m on ree
storetion are complicated by the fact that animals which have re-
ceived previous treetment with thyroid 'dould not withstand the loss
of 70% of the liver.' (Higgins'S3). It was necessary to perform
partial hepatectomy before commencement of thyroid administration.
The administration of thig thyroid ration to control animals caused
an increase in proportional and absolute body weight, and the restore
ing livers under the influence of thyroid restored this increased
weight (aprr ox.. 265% greater.) Appreciable deviation from the normal
réstoration curves did not occur until the end of the first week of
restoration, the rate being most accelercted during the second week.
in these animals which were not operated on, the administration of
thyroid had no effect on liver weight until the seoond week of treat-
ment. This lag, compared to the very brief one in normal restor~
ation may indicate that if the thyrold plays a role in normal re«-
storation, it may be indirect. On the other hand, Sternheimer,
(Sternheimer '39) has reported a great qualitative increase in
mitoses in the liver only 48 hours effer the administration of a

large dose of thyroxine. Thig ig another instance of a conflict
of cytological and gravimetrio interpretations, His data also

indios te a more rapid weight response of the liver to thyroxine (in
this large dosage: 4 mg/kg.) It has also been reported that there is
a diminution. of the thyroid glands after partial hepatectomy.
(Schmidt & Richter '41, Kellaway, et al, Endocrinology '45, A Rex
lation between Thyroid & Liver.)

This 'orucial experiment’ that must be performed clearly
ig the restorative capacity of the liver after the thyroid has been
removed, preferably with the Feeding of standard doses of this hormone.
Thig has not been done.

The effects of the administretion of male hormon+s to rats
and dogs’ livers have been tested. (Hall & Korenchevsky '36, Black»
man et al '44,) While relative hyrertrophy seema to occur, scain no
cytological observations have been mace, and the possibilty of
involved indireot effeots makes unfeasible an extended analysia.

In view of the well-established function of the liver in the inact-
ivetion of the estrogenic hormones, the effects of these hormones
must be considered, but no sconolusive reports have as yet apreared.

A hormonal regulation of liver could be demonstrated in
parabilotio pairs of animals, an attempt to do which is in progress
in these laboratories, In toad larvae which have been parablosed
at an early developmental stage, the extirpation of the liver in
one palr ig claimed on the basig of one experiment to cause an
enlargement of the liver in the other. (Yamada '33-) The appli-
Qability of this observation as a proof of a hormonal mechanism
in mammals in the adult ~hase would be unnecessarily sneculative.

Thus fer the only egents which will stimulate mitosis in
the liver are a) the operation of partial hepatectony, and b) the
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administration of thyroid. One other agent of this sort has been
described: the administration of suspensions of homologeus liver
caused an apoarent increase in mitotic rate of the intact liver
nearly comparable to thet after partial hepatectomy. If given to

a@ partially hepatectomized animal, mitotio rates of 15% those ue=
ually found in the restoring liver are seen. Unfortunately, the
method or expression of mitoses ae average number per section is
unreliable to. variation in cell size, and in pronortion of CT cela&s,
etc., in the areas counted, and the figures published show such
varisbility that a statistioal analysis seems desirable. | (ieJunkin
& Brevheus '31.) The implications that these observations hold for
normal restoration is not clear, since it is difficult to conceive
how the quantities used of such material could oecur normally or
after partial hepatectomy. Isolation of the active component would
be very interesting. Apparently indevendently, Narshak ('45b.) has
studied the effecte of ‘chromatin’ vreparations from liver on the
mitotic rates of restoring liver, 24~27 hours efter resection. Uife
fortunately the method of counting is subject to a Large error, as
demonstreted within the paper itself, and the normal mitotia rate
is also quite variable in these restoring livers, so that the state
istical justification of his conolusions 1s at best questionable.
It is claimed, however, that the fresh chromatin preparation ia the
moet active component, a large series of other compounds having no
effect. Again the besring that thie might have on normal restoration
is not clear, although the administration of exogenous chromatin
may be increasing the growth rate of the restoring liver by. lessen-
‘ing the possible limiting factor of nucleic acid rate of synthesis.

Thus while chromatin may be a valuable accessory factor, it has net

been shown to be the trigger which sets off mitosis, and unfortunately
~ 14 =

‘data on the effect of these fractions on mitotio rates of intact
livers are not presented.

There are several papers on changes an the blood chemistry,
end on the chemistry, enzyme content and turnover rates of various
gomponents in restoring liver, which cannot be reviewed in detail.
Ihe chief elterations appear to be an 4ncreased blood globulin,
decreased albumin, and a very high turnover in P= end in mucleis acid.
A bibliography to thie phase of the subject is apvended to the list
of references sited. .

The mechanism of liver restoration 1s, thus, seen to be in
@ nignly controversial state, and the need for furtner res :eron ev
ident, particularly in the possible role of humoral intermediates,
be they specific hormones, or metabolites ordinarily disposed of by
the liver, and accumulating in ite reduction. fne theoretical and

elinicsl importance of such an advance is obvious.
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REFERENCES CITED

Addis, T., L. J. Poo, & W. Lew, JBC 116: 343-353 1936. The rate
ef protein fermation in the orzens and tigssues of the body.

Blackman, 9.5S., 0.3, Thomas & J.5. Howard, Bull J Honk Hosp 74:
O21~-34 1944. The effeot of testosterone vroplonate on the arterial
blood >ressure, kidneys, urinery bladder and livers of crowing

_ dogs.

Brues, A.M. J Physiol 868: 63-4 1936. ‘he efrect of colchicine on
regenerating liver.

Brues, A.M., DR Drury, & M.C. Brues, Arch Path 22: 658-73 1938.
A quantitative study of cell growth in regenerating liver.

Brues, A.M. & B.B. Marbel J Exp Med 65: 15-27 1937. An analysis
of mitogia in liver restorations.

Cameron, G R, J Path Bact 41:1 283-8 1935. Liver regeneration and
biliary obstruction.

& C. L. Oakley J Path Bact 38: 17- 1984 Trenge
plentation of the liver.

Deysteh, L. J. AJP 132: 713-24 1941, The nature and location of
sphineter mechanism in the liver as d8termined by drug actions
and vascular injesotions.

Fishback, F.C. Arch Path 7: 955-77 19°99. A moreholosic study of
regeneration of the liver after partial remcval.

Fraenkel-Conrat, H.H., M.E. Simoson & R.M. Evans, AJP 155: 398—
405 1341. Effect of vurified situltary vrevaurationg on Liver
weights of hypovhyseotomized rats.

Franseen, C.C., A.M. Brues & R.L. Richards, Endoor 23: 292-301
1933. The effect of hysonhysectomy on the restoretion of the
liver following partial hevatectomy in rata. -

Griffith, F.R. and F.E. Emery, AJP 95: 20#34 19.30. The vaso~
motor control of the liver circulation.

Grindlay, J.H., F.J. Herrick and F.C. Mann, AJP 122: 489-96
1941. Measurement of the blood flow of the liver.

Hall, K. & ¥. Korenchevsky, Br Med J 4025: 438-41 1933. Changes
in the liver of male rats after castration and after injeotisona
of sexual hormone.

Handler, P. & F. Bernheim, JBC 148; 649454 1943, Effect of choline
defistenoy on fst content of regenerated livar,

Higgina, 4.4. Arch Path 16: 226-231 1933. Uffects of fe-ding des-
icested thyroid gland on the restoration of the liver.

Lior O23 t@ Anderson, RIM. ib712:186~-202'1931. Restoration: of
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sl.

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BGe

» 11 «

ib 14: 42-9 1933. Restoration of the liver
after partial surgical removal and ligation of the bile duct in
white rets.

& Ingle, D.J. An Reo 73: 95-104 1939. Regeneration
of the liver in hypophysectomized white ret.

; Mann F.C, and J.T. Priestley, Arch Path 14: 491-
97 1933. Restoration of the liver of the domestic fowl.

& J.T. Priestley, ib. 13: 573-83 1932. Restora-
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