Paper - Functions of the liver in the embryo
|Embryology - 19 Jun 2019 Expand to Translate|
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|John Ernest Frazer (1870-1946) also wrote on several other embryology topics, as well as published an embryology textbook. Our current understanding on liver development and function is far more detailed.|
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Functions of the Liver in the Embryo
By |J. Ernest Frazer, F.R.C.S. (Eng.),
Professor of Anatomy in the University of London
A strange statement was made by Harvey in the sixteenth chapter of his immortal Ewercitatio Amdomica de Motu Cordis. He says here: “Hinc in Embryone pene nullus usus jecoris, unde. . .etiam in prima foetus conformatione jecur posteriusfieri contingit, et nos etiam in foetu humano observavimus perfecte delineata omnia membra, imo genitalia distincta, nondum tamen jecoris posita pene rudimenta.. . .”
|Hinc in Embryone pene nullus usus jecoris, unde. . .etiam in prima foetus conformatione jecur posteriusfieri contingit, et nos etiam in foetu humano observavimus perfecte delineata omnia membra, imo genitalia distincta, nondum tamen jecoris posita pene rudimenta.. . .||The embryo has almost no use of the liver, where. . .also in the fetal liver was established after it happens, and we also observed perfectly meted out to all members of the human fetus, or even genitals are distinct, yet there were elements of the liver ... .|
One cannot help wondering whether the meaning which appears here on the surface really expresses Harvey’s intention, and that he meant to convey the impression that the organ is a small thing and of no account in the earlier months of development; for it does not seem possible that so acute an observer would have been ignorant of the great relative size of the liver in these months. No doubt, from the view-point which he occupied at the time, there seemed to be no necessity for a large organ, which would account for the first sentence quoted above; but, with a man of this calibre, it could not explain the second, and one seems almost driven to assume that he was deceived by the condition of his specimens and the friability of the liver—a very unsatisfactory explanation.
The undeniable fact that the liver is of such great relative size in embryonic life suggests that it performs some function then which is associated with its size. The Galenical concept of the liver as the fount and origin of the blood was seemingly laid to rest by Harvey, but, in a sense, it has stirred again, in the qualitative, if not quantitative, blood-forming activities now known to be at work in the organ. But this function does not account for the size of the early liver. It goes on after the liver has altered its rate of growth, and ﬂourishes even after birth. Also the biliary functions of the gland are not established before the relative maximum size is passed, and it is hard to see any. connection between them and the great embryonic growth. There seems, in fact, to be only one thing in the life history of the embryo which is directly associated with the greatest size of the liver, and which is coexistent and coterminous with it: I refer, of course, to the extra-abdominal position of the gut, terminating by its passage into the abdomen and its subsequent growth there. This connection has often been recognised, and the liver has been credited witlf the pushing of the intestine out of the abdomen at one time, and, on the other hand, has been said to be the main power at work in pulling it back again later on, but there has not been, so faras I am aware, anything more than general suggestions that these things may be so, nor any coherent effort to show by what means they could be so. When working with Dr Robbins on the rotation of the gut, I found myself adopting more defined and, I think, reasonable views about the part played by the liver in the matter. In the paper published at the time in this Journal I mentioned these views shortly, in so far as was necessary for the purpose in hand: in this communication I propose to give a fuller account of what, in my opinion, this part may be considered to be.
For convenience, the subject may be considered under several different headings.
1. The state of the embryonic liver
As is apparent at once on examining sections, the liver of the embryo is a loosely built organ, very vascular. It consists of solid material and a considerable amount of ﬂuid. The solid portion, leaving out of account blood cells which vary directly with the amount of blood, is a fixed quantity. The ﬂuid constituent of the liver can be divided into that within the vessels and that outside them. The former, the blood, can by its escape into its natural extra-hepatic and extra-abdominal channels, lead to a rapid and sensible diminution in the total bulk of the organ, the unchanged quantity of solid constituent remaining. The liver grows by increase of its solid columns and of the vascular spaces between them. It grows in correspondence with the growth of the abdominal cavity, and fills up every available corner of that cavity, lying beside the median mesenteric septum and the bursa omentalis. But there does not seem to be any reason to suppose that in its growth it exercises any pressure whatever on neighbouring structures: on the other hand, reasons for thinking that it does not do so may be seen in the state of the bursa omentalis, the bold transverse curve of the duodenum, the processes of the Wolffian bodies, the thin-walled veins in the organ and outside it, etc. I am not aware of any evidence of pressure being exerted by the growing liver, and, during the examination of all stages, the impression has formed itself in my mind that the organ in its growth might almost be likened to a very viscid ﬂuid slowly running, without pressure, and ﬂowing into interstices and filling up spaces: of course it is not a simple viscid ﬂuid, but such an idea will illustrate fairly well, in some ways, the conception I have formed of its mode of growth" and the way it acquires its form. It is instructive to examine places where (as may be seen for instance here and there beside a well-developed Wolffian body) a process of the liver has passed in through some narrow chink or fissure, into a wider space, so that a small enlargement is torn off at its narrow neck when the organ retracts on dehydration: in these cases there has plainly been extension of the liver without any ﬂattening of the structures bounding the chink, as if the liver had “ﬂowed” into the recess rather than pushed its way into it.
The conception of a liver growing in this way, composed of solid columns with intervening spaces filled with ﬂuid which is able to vary in amount, entails certain corollaries. The growth goes on pari passfi with the growth of the belly cavity: but if the solid parts grow faster than the cavity, it follows that the ﬂuid parts must become relatively less, and vice versd. So, if we accept the general truth of Jackson’s statements about the falling rate of growth of the liver after the first part of the third month, it means that the venous spaces in the organ at this time are comparatively large, and getting relatively larger as the rate falls.
2. The mechanical bearing of this state
I have, so far, seen no reason to believe that the liver is in any Way responsible, through its increase in size, for the presence of the gut in the umbilical sac. I have not been able to satisfy myself about the matter, principally because my earlier specimens (under 5 mm.) are not sufficiently well preserved to provide reliable data, but I have a decided impression that the extra-abdominal position of the gut has more to do with the slow growth of the belly-wall than with any intra-abdominal condition: that there is no room in the abdomen at first for anything but the Wolfiian bodies and the umbilical veins: that this is due to the small size of the cavity from the small extent of the walls: that consequently the lengthening intestinal bend is effective only in the direction of the vitello-intestinal duct: and that the formation of the dorsal mesentery, when its explanation is given, may possibly throw more light on the umbilical position of the gut than will any researches on the liver. Or, from a point of View a little different, it might be said that the abdominal wall closes in behind the umbilical gut, and thus this part of the bowel is not extruded from the belly, but lies outside it ab initio. Whether these views turn out to be true or not, there is little doubt that the gut is already outside the belly wall by the time the liver begins its most effective growth, and, to my mind, this growth is called forth by, and is an expression of the necessity for filling the space caused by, the increasing area of wall—increasing too late to enclose the bowel within it. In other words, the liver growth would be more rightly looked on as an indirect consequence of the external position of the gut, than as the cause of the gut assuming this position.
But, though it may not cause the extrusion of the bowel, it would seem that the presence of the growing liver leads to the continued extra-abdominal existence of the viscus. The ‘organ grows pari passzi with the cavity, which it fills, so that the walls are supported by it against the external amniotic pressure. This equalisation of pressure permits the other viscera, whether inside or outside the belly, to live in “a state of rest” in their respective situations.
There can only be inverse variations between the two constituents of the liver mass, if this is to keep pace with the growth of the cavity: such variations will naturally only be possible within limits. So long as the limits are not exceeded, or perhaps too closely approached, the condition of equilibrium between the internal and external viscera will remain: if one could imagine such a thing as the liver failing altogether to develop, while the abdominal walls grew at their usual rate, it would not seem possible that the formation of the intestinal coils could go on outside the cavity; for the cavity must be filled, and, if the liver fails to perform this function, it ‘can only be carried out by the intestine. Looking at it conversely, the development of the coils outside the belly is an indication that the liver growth fulfils efficiently the task of occupying the available cavity and equalising the intra-abdominal and extra-abdominal pressures.
3. The mechanical state towards the end of the first stage
Towards the end of the first stage, when the umbilical gut is nearly ready to enter the abdomen, the rate of growth of the liver, i.e. of course, of its solid parts, begins to fall behind that of the cavity. This was pointed out by Jackson some years ago (Anat. Record, 1909) and there can be little doubt, I think, that his general conclusions are correct, although, as we shall see later, there may be reason for modifying the details of his figures. As the rate of solid growth falls, and as the mass must still fill the cavity, it follows that the relative amount of blood in the organ must be increased: it is evident that, the decreasing rate of solid growth persisting, there will be both actual and relative increase in the amount of blood, and distension of its vessels. One can imagine that at first this change in the relations between solids and ﬂuids would not make itself felt away from the liver, and that then any indications of difficulty in keeping pace with the growth of the cavity might be met by falling in of the walls to some little extent, but, if the process continues, there must come a time when the vessels and the solid columns between them are stretched to their utmost extent, and any further reply to the demands of the growing cavity becomes impossible. Whether the process ever does proceed so far as this or not, I have no means of deciding, nor does it really much matter from our present point of view; it is sufficient to understand that the liver now contains a large and unusual amount of ﬂuid, and may be considered to be “stretched” to a considerable extent, a condition necessarily associated with lessening of the tension inside ‘the abdomen, compared with that outside it and away from liver inﬂuence.
4. The necessary conditions associated with the entrance of the gut into the abdomen
This movement of the intestine is rapid. As I conceive it, it is probably only a matter of minutes. It is brought about by a relative rise in extraabdominal pressure, due to some fall in intra-abdominal tension. The mass of gut and mesentery in the sac may perhaps offer at first some resistance to the movement, aided by the small size of the aperture through which they must pass, but‘ when once the movement starts there is no reason why it should not continue. The nature of the movement and its order have been already dealt with in the previous paper, and need not detain us now.
It is evident that the introduction into the abdomen of such a comparatively large mass as that which occupies the umbilical sac calls for provision of space for special accommodation. This space must be provided as it is required: it cannot exist as an unoccupied part of the cavity before the entry of the intestines, for this would mean either a vacuum or a collection of ﬂuid which would change places, so to speak, with the gut, a supposition at variance with the mechanical causes of the entry on the one hand, and, on the other, with the conditions of both umbilical and abdominal regions as found in the embryo. Moreover, it seems necessary to suppose that the provision of the space must take place without the exercise of any force on the part of the intestine: the gut cannot be thought to compress any organ or organs which it finds in the abdomen, for this would mean that it makes its way against resistance, a thing hardly conceivable.
I suppose that a common idea of what takes place might be expressed by saying that the lessened growth of the liver and Wolffian bodies leads to a fall in “intra-abdominal tension” which is met by the walls falling in below the liver; then, when the gut comes in, space is provided by the bulging of the slack of the walls. To my mind this conception is open, without considering other points, to the fatal objection that it does not allow for the play to their end of the factors causing the movement. Even if one were to admit—which I would hesitate to do—that such elastic recoil were possible in these walls, a little reﬂection will show that the exercise of this quality by the walls is not compatible with a complete return of the intestine: the force supposed to be leading to the return would decrease rapidly as the walls were relieved of their inverted strain by the incoming bowel, a state of quiescence ought to occur very soon, and it is impossible to conceive the movement going on to a bulging of the walls, unless we postulate an insistence (on the part of the bowel) on finishing the job when it has once started to enter the belly—a form of vital activity hitherto unsuspected. For my part, I cannot help feeling that the walls are incapable of playing any but a subsidiary part in the movement, and that they are mainly passive so far as it is concerned, perhaps indirectly aiding (as will be mentioned later) in the beginning of the movement, but exercising no inﬂuence on its continuation or completion.
We might say, then, that the explanation of the conditions immediately preceding, accompanying, and following the ventralisation of the bowel must take account of the necessity for providing potential accommodation, for converting this into actual accommodation as and when it is required, for allowing this to take place without calling for any pressure from the bowel, and for connecting all this with the mechanism which leads to the intraabdominal movement of the gut. In addition, the factors causing the change of location must be capable of continuous action till the movement is completed.
==5. The role of the liver in meeting these necessities--
It has been pointed out above that the liver, if its rate of growth falls and it yet fills the cavity, must be in what can be conveniently termed a “ stretched ” state as the end of the first stage approaches. With certain and evident reservations, it may now be likened to the lung in the adult thorax, a viscus also in a “stretched” condition. The lung exercises a pull on the thoracic wall which is increased as the thorax is enlarged: this is the same as saying that the intrapleural pressure is further lowered. So long as the liver grows pari passzi with the belly its conditions differ from those of the lung, but when it becomes “stretched,” it is comparable with that organ: it begins to exercise a pull on the abdominal walls, and, as these enlarge, the intra-abdominal pressure is lowered. If a tube were inserted into the pleura, water or air would be drawn into that cavity through it when the thorax enlarges: in the case of the abdomen there is alreadylan umbilical tube connected with its cavity, and its contents similarly tend to be drawn into the abdomen as the intraabdominal pressure falls: these contents are coils of gut and mesentery. The immediate cause, then, of the ventralisation of the intestine is the relative increase in external pressure arising as the result of lowered internal pressure, due to the “stretched” state of the liver as the walls grow.
Also, as the pull of the lung would not be satisfied by the passage through the tube of a few drops of water, but would lead to the taking in of a quantity suflicient (if obtainable) to allow its collapse, so the retraction of the “stretched” liver would continue in front of the entering intestines, without pressure from them and merely in virtue of its own power of recovery of its natura “unstretched” condition. This, it is hardly necessary to point out, implies that the excessive blood occupying the dilated spaces is expelled from the liver into the vena cava, so that the organ is reduced in size and the original relation between solids and ﬂuids restored. Thus it may be said that the intestinal presence enables the liver to retract, and it is the tendency to retraction, essentially inherent in its distended and “stretched” condition, which initiates and carries on the movement of the bowel. Hence the liver might be described as retreating before the intestine, without pressure, as a lung retreats when some foreign substance begins to occupy the pleural sac.
Whether the tendency to retraction is wholly satisfied or not by the presence of the gut is, of course, a matter at present impossible to decide. The rapid growth of the bowel after the event seems to point to an answer in the negative, and it is conceivable that the dorsal shifting of the originally umbilical colon may indicate the same. The apparent rapidity of the movement and its complete nature, with the great rarity of partial failure, also point in the same direction, unless we are willing to admit a most accurate and delicate adjustment between the retractile potentiality and the intestinal mass. Unfortunately, and in the nature of things, it is only possible to bring forward as assumptions the functions which are claimed here for the liver. Experimental proof of the assumptions is, of present necessity, lacking. I hope that it may be possible to carry out some experimental observations on other embryos when the opportunity serves, but, as nearly all my human material reaches me in formalin or alcohol, it has not been possible to use it in this way. But the examination of ordinary prepared specimens yields certain results which are of importance in this connection.
In the first place, there can be no doubt that the liver occupies all available space in the abdomen of the living or recent embryo. Reconstruction models show this clearly: for example, the model of the liver of a 28 mm. specimen, made for the original work, demonstrates by its markings all the organs with which it was in contact before dehydration. In this way it can be shown indubitably that, as in all other specimens after the youngest, it reached to the extreme caudal limit of the abdominal cavity: yet the sections exhibit the lower portion of the cavity as quite free from any trace of liver structure. This is the usual and necessary concomitant of preparation. Dehydration of the liver implies its contraction through the removal of ﬂuid, and, as its attachment is above, its retraction must show its effect mainly below. It follows from this that, though the shape and relational markings are fixed and preserved with a general fidelity, the bulk of the reconstructed organ is less than it should be if it is to be taken as an absolute proportionate enlargement of the actual liver, and the ratio of its mass to the abdominal cubic content is false without considerable correction. It was from this standpoint that I took exception, earlier in this paper, to the acceptance of Jackson’s measurements and ratios as calculations accurate in detail. My objection is, of course, only to their acceptance without due correction for the effects of dehydration, and does not apply to his general conclusions. I have tried to avoid dehydration by making use of Salkind’s “lead gum” method, but this was not successful in my hands and was abandoned owing to wastage of valuable material: in other hands it might succeed and yield good results.
The shrinkage of the liver resulting from dehydration is very suggestive, in that it shows how space can be provided in the abdomen by loss of ﬂuid from this organ. But the conditions under which ﬂuid is removed in this case differ widely from those that would be present if ﬂuid were taken out as blood, through the vessels. In the first case the alcohol replaces the water in the vascular spaces, so that no collapse of these spaces takes place, while its action on the solid columns is further modified by their previous fixation: in the second case there is nothing to replace blood withdrawn, so that, if it is withdrawn, the solid material round the spaces must fall in, and the total bulk of the liver must be decreased by so much. It would seem, then, that the contraction due to dehydration would not be so marked as that brought about by the withdrawal of a relatively small quantity of intravascular blood, and the possibilities of this last method are, of course, much greater; indeed, the maximum effect would be produced by complete exsanguinification of the organ, a process which never occurs but which, if it did occur, would probably lead to reduction to about half the original bulk.
The following observation is of interest in connection with this aspect of the condition. Two models were made from an embryo of a stage just preceding that in which ventralisation of the bowel might be expected to occur. One was a “cast” of the abdominal space from which the liver had retracted, care being taken to cut wide of the various structures there and not to include any part of the space which seemed in any way to have come into being as between two organs originally in contact, so that as far as possible only the effect of liver contraction might be gauged: if any doubt arose, it was always decided against the inclusion in the model of that part of the cavity concerned, and in this way a cast was obtained which was not, I think, larger than the liver space required, but was in all probability considerably smaller. The second model represented the umbilical mass of gut and mesentery: to obviate the shrinkage of these, the outline of the containing sac was taken in place of its contents, as these had during life filled the sac, and in this way a mass model was obtained which might with great fairness be said to be approximately equal to——if not larger than—the bulk of the contents of the sac during life. The bulk of each model was then found by displacement. The result gave the ratio between the cavity and the umbilical mass as 28: 31. As already stated, the first measurement is probably too small, and the figures, I think, would more truly be expressed as about of the same value, but the interest of the observation really lies in the indication afforded by it of the amount of contraction which occurs in the liver as the result of extraction of ﬂuid. It is evident that the necessary accommodation for the incoming intestine could be provided, probably altogether, by shrinkage as the result of removal of ﬂuid from the solid columns, and hence it would seem that it could be obtained easily by the more definite and complete retraction got by withdrawal of blood from the liver vessels, if this withdrawal takes place: if the withdrawal does not take place, there does not seem to be any mechanism through which the liver can lessen its bulk, and lessening of its bulk is absolutely necessary if the intestines are to find place in the abdomen.
These points just mentioned are important ones, as they bring forward the fundamental facts on which comprehension of the mechanical conditions depends: the abdominal cavity is fully “occupied” up to the entry of the gut, it must be occupied during the passage, and yet accommodation must be provided—and of all the structures which affect the cavity the liver is the only one even remotely capable of fulfilling these functions.
If the views advanced in this paper are confirmed by further experience and prove to be substantially correct, we have in them some explanation or reason for the rapid rate of growth and size of the liver in the embryonic period: it allows the abdomen to grow while the intestine develops outside it, it supplies the means by which the intestines are brought into the belly, and it provides the accommodation for them therein, as and when it is wanted. No suggestion is offered concerning the apparent necessity for the extraabdominal development of the gut; it is even conceivable that this position of the bowel is required, for some deeper reason, to allow the liver to develop. But, however this may be, there is in my mind no doubt about the mechanical relationship between the two conditions, as set forth above. This way of looking at the questions seems to me to offer the only completely satisfactory solution of their problems, congruous with all the conditions present.
We might therefore divide the intra-uterine life of the liver into two main stages: the embryonic, in which its functions, other than growth, might be termed mechanical, and the foetal, after the ventralisation of the bowel, when the processes of bile-formation and of other bio-chemical activities are initiated.
The excessive development of the liver in its early stages has now some sort of raison d’étre; it is otherwise apparently meaningless, for we see even atrophy and degeneration of some parts at later stages. Moreover, not only is the accuracy of the general statement quoted from the Ewercitatio upset by the fact that the liver reaches a great size in the early stages, but the reasons advanced for this great size, if they are accepted, dispose of the particular assertion contained in the first sentence of the quotation. There can be no question about the truth of the statement that the gut is extra-abdominal and becomes intra-abdominal, nor that the mechanical conditions underlying and allowing these states and changes call for explanation, and, as already stated, the only completely satisfactory and satisfying explanation would seem to be that which brings in the liver in the ways advocated in this paper.
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